Compounds as inhibitors of sodium channels

ABSTRACT

Methods and small molecule compounds for inhibition of sodium channels are provided. One example of a class of compounds that may be used is represented by the compound of Formula (I) or a pharmaceutically acceptable salt, N-oxide or solvate thereof, wherein A, B, D, R, R1, R′1, R2, R3, R4, R5, R6, R7, R8 are as described herein.

GRANT INFORMATION

This invention was not made with Federal government support.

FIELD OF THE DISCLOSURE

The disclosure relates generally to small molecule compounds and morespecifically to derivatives of stereochemically defined phenoxy propan-2amines and deuterated analogs for their use in cardiovascular andcentral nervous system diseases.

BACKGROUND OF THE DISCLOSURE

Cardiovascular disease is a leading cause of deaths in the UnitedStates. For example, heart attacks are the leading cause of death in menand women in the United States during 2010 with a total economic impactof $40 B/year. 50% of individuals over the age of 65 suffering heartattacks die within 5 years of a heart attack. Despite this prevalence,options are limited. Treating arrhythmia in individuals before or afterheart attacks and arrhythmia with Long QT (LQT) prolongation is also anunmet need. Thus, there is a major unmet medical need for thedevelopment of selective and inexpensive targeted treatments forcardiovascular disease.

The blockade of voltage gated sodium channels that inhibits thegeneration and propagation of an action potential is the mechanism thatlocal anesthetics, antiarrhythmics and anticonvulsants preventpathological firing of action potentials in excitable tissues. Forexample, Mexiletine, a well-established orally effective antiarrhythmicdrug of the IB class is effective in treatment of muscularhyperexcitability of myotonic syndromes including ones with abnormalmembrane excitability and delayed muscle relaxation after voluntarycontraction. Sodium channel myotonias, paramyotonia congenital andhyperkaliemic periodic paralysis and epilepsy are among many diseasesrelated to sodium channel mutations. The therapeutic effect ofMexiletine is directly associated with its ability to blockvoltage-dependent sodium channels present in cardiac and skeletal musclefibers. Use-dependent blockers of sodium channels stabilize the channelsin the inactivated state and allows a greater potency on tissuescharacterized by excessive excitability including myotonic muscles withnon-physiological phenotypes of sodium or chloride channels. The on andoff rate of binding to the sodium channel determines the efficacy of thedrug as well as the relative degree of toxicity. If the molecule bindstoo long, this interferes with sodium channel excitability. ForMexiletine, the potency of blocking the sodium channel can be correlatedto lipophilicity of the molecule. The sodium channel target ofMexiletine that has a center of chirality has shown moderate or lowstereoselectivity.

Mexiletine has shown clinical utility to decrease abnormal sodiumchannel discharges in myotonic syndromes. Mexiletine is the leadingagent to treat cardiovascular disease in dogs. Despite the promise,Mexiletine has significant drawbacks. For example, the dose used foranti-myotonic effects are as great as those for exerting antiarrhythmiceffects and can induce or worsen conduction defects. In addition, at therelatively elevated doses and multiple administrations due to itsclearance required for therapeutic action, Mexiletine can have sideeffects on the central nervous system. Electrophysiological andbiochemical evidence points to block of sodium channels in the centralnervous system. For example, local anesthetics inhibits batrachotoxin A20-alpha-benzoate and alters stereoselective binding of cocaine tosodium channels in the brain. After administration to animals,Mexiletine causes seizures and nausea. Thus, because the recommendeddose to treat arrhythmia and myotonic patients are in the same range,adverse effects on both the cardiac and central nervous system arepossible. Selective stimulation of different sodium channels may haveutility for CNS diseases or seizures. In addition to effects on sodiumchannels, Mexiletine and other related drugs possess off-target effectson the potassium channel.

Despite the fact Mexiletine is a very old drug, little work has beendone to re-engineer Mexiletine to remove side effects. For example,Class Ic anti-arrhythmics were examined in the CAST and CAST II studies.The results showed that treating patients with Class Ic sodium channelblockers post MI decreased arrhythmia in the short term, but led togreater instances of arrhythmia-related deaths in the long term. ClassIc anti-arrhythmics were chosen because other anti-arrhythmics (i.e.,Class Ia and Ibs including Mexiletine) had been shown to not suppressarrhythmia or had adverse effects that precluded their use. In thecurrent clinical setting sodium channel blockers are not used for thetreatment of arrhythmia.

What is needed is a more potent compound with greater potency againston-target sites and less potency against off-target sites. For example,a desirable improvement on Mexiletine would be to optimize the usedependence and the refractory period effect or decrease the inhibitionof potassium (hERG) channel effects. The basis for effecting this couldbe changing the 3D structure or introducing new pharmaceuticalproperties. Until our work, no phenotypic cell-based assay was availableto discern these effects. Arrhythmogenic agents can be identified innormal and LQT3 human patient-derived cardiomyocytes using avoltage-sensitive kinetic imaging cytometry assay. A phenotypic screenin human cardiomyocytes provided powerful information to ascertainon-target and off-target effects in highly relevant human cells.Important metrics of compound efficacy and safety were obtainedincluding: action potential delay (APD) shortening (i.e., IC₅₀ foron-target effects), APD prolongation (i.e., IC₅₀ for off-targeteffects), early after depolarizations (EADs that provide evidence ofarrhythmogenicity) and cessation of beating (i.e., a marker of acutearrhythmogenicity/toxicity). Concurrent evaluation of these metricsunderscores the value of this approach using a whole-cell physiologicalapproach. Results from our work provided several new compounds thatshowed significantly less arrhythmogenicity than Mexiletine in normaland LQT3 patient-derived cardiomyocytes. Compounds evaluated byelectrophysiology confirmed and extended the results. Together, thesedata showed that chemical modifications to different portions of theparent Mexiletine decreased arrhythmogenic liability while modificationselsewhere affected on- and off-target effects. For example, unexpectedselectivity on sodium and potassium channel inhibition by Mexiletineanalogs was observed due to novel substituents. Also, unanticipateddecrease in metabolism was observed by moving certain substituents ordeuteration of Mexiletine likely due to unexpected changes inregioselective metabolism or structural aspects.

Mexiletine is relatively rapidly metabolized by hepatic enzymes and isrelatively rapidly cleared in vivo. Multiple doses of Mexiletine arerequired for human efficacy because of metabolism, clearance andtoxicity. Replacement of metabolically labile C—H bonds withmetabolically less labile groups containing C—Cl or C—F or C-D or C—CF₃or C-aryl or C-cyclopropyl groups afforded more bioavailable compounds.Compounds were chemically (t_(1/2)>30 days) and metabolically (hepaticmicrosomes+NADPH) stable (human t_(1/2), >60 min). In contrast toMexiletine, select compounds showed no acute toxicity in mice in vivo.In a (24 hour) toxicity study, compounds administered to mice (100 or200 mg/kg, (i.p.) did not produce seizures. In contrast,Mexiletine-treated animals (100 or 200 mg/kg, i.p.) showed death,seizures and other behavior issues. The LD₅₀ for Mexiletine (114 mg/kg,i.p.) in mice shows the therapeutic window is narrow. In contrast,analogs were non-toxic and well-tolerated in vivo.

Compounds described herein are drug-like small molecules and havecharacteristics that make them very attractive small molecules drugs.For example, analogs formulated as salts have excellent aqueoussolubility and improved bioavailability, are chemically andmetabolically stable and are non-toxic and highly potent and selectivesodium channel inhibitors.

SUMMARY OF THE DISCLOSURE

In one aspect, the disclosure provides a nontoxic compound of Formula Ior stereoisomers or a pharmaceutically acceptable salt, N-oxide orsolvate capable of selectively inhibiting sodium channels:

A compound of Formula I:

or a stereoisomer, tautomer, isotope, or salt or thereof,

wherein:

A, B, D are independently Carbon or Nitrogen;

R₁ is selected from the group consisting of hydrogen, deuterium, methyl,trideuteromethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₆-C₂₄)aryl, and(C₅-C₂₄)heteroaryl, wherein (C₆-C₂₄)aryl and (C₆-C₂₄)heteroarl areoptionally substituted with 1 to 5 R₈ substituents independentlyselected from the group consisting of deuterium, halo, methyl,trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino,(C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano,nitro, and (C₁-C₆)alkylsulfonyl;

R₂ is selected from the group consisting of hydrogen, deuterium, methyl,trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloheteroalkyl, 2-(C₁-C₆)alkoxyethyl,2-hydroxyethyl, 2-(C₆-C₂₄)aryloxyethyl, bis(2-methoxyethyl),(C₁-C₆)alkoxymethyl, 2-(C₃-C₆)cycloalkoxyethyl, (C₆-C₂₄)aryl, and(C₆-C₂₄)heteroaryl, wherein (C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl areoptionally substituted with 1 to 5 R₈ substituents selected from thegroup consisting of deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro and and(C₁-C₆)alkylsulfonyl;

R₃ is absent if A is Nitrogen, or if A is Carbon R₃ is selected from thegroup consisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl;

R₄ is absent if B is Nitrogen, or if B is Carbon R₄ is selected from thegroup consisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl;

R₅ is absent if D is Nitrogen, or if D is Carbon R₅ is a substituentselected from the group consisting of hydrogen, deuterium, halo, methyl,trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino,(C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano,nitro, and (C₁-C₆)alkylsulfonyl;

R₆ and R₇ are independently selected from the group consisting ofhydrogen, deuterium, halo, methyl, trideuteromethyl, trifluoromethyl,2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy,(C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,(C₆-C₂₄)arylamino, cyano, nitro, and (C₁-C₆)alkylsulfonyl.

R₁ is independently substituted S and/or R isomeric forms and/or racemicforms and can also be substituted with a deuterium at the center ofchirality.

In another aspect the disclosure provides methods for stereoselectivelysynthesizing compounds inhibiting sodium channels, comprising contactingcells with a aryloxy propan-2-amine-based compound of Formula I in theform of a free base or a pharmaceutically acceptable salt, prodrug,hydrate, solvate or N-oxide thereof, wherein A, B, D, R, R₁-R₆, are asdescribed above.

In another aspect the disclosure provides methods for stereoselectivelyinhibiting sodium channels, comprising contacting cells with a aryloxypropan-2-amine-based compound of Formula I in the form of a free base ora pharmaceutically acceptable salt, prodrug, hydrate, solvate or N-oxidethereof, wherein A, B, D, R, R₁-R₆, are as described above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Initiation of Early After Depolarizations-Mediated EctopicVentricular Beats and Ventricular Fibrillation in an Isolated PerfusedAged Rat Heart Exposed to hydrogen peroxide.

FIG. 2. Complete resolution of all forms of arrhythmias to normal sinusrhythm 30 min after perfusion of Compound (R)-82 (10 μM) in an IsolatedPerfused Aged Heart in the presence of hydrogen peroxide.

DETAILED DESCRIPTION OF THE DISCLOSURE

The following terms, definitions and abbreviations apply. Abbreviationsused herein have their conventional meaning within the chemical andbiological arts.

The term “lipophilic” refers to moieties having an affinity for lipidsand other fat-like substances, tending to combine with, and capable ofdissolving, them.

The term “sodium channels” refers to voltage-dependent sodium channelsin cells.

The term “mutant sodium channels” refers to variant sodium channels incells with traits associated with abnormal or pathophysiologic behavior.

The term “myotonia” refers to a condition of cellular hyperexcitabilityand abnormal membrane excitability and delayed muscle relaxation aftervoluntary contraction, where the cells have lost specific structural,functional, and biochemical cell-cycle checkpoints.

The term “patient” refers to organisms to be treated by the methods ofthe disclosure. Such organisms include, but are not limited to humans orother animals. In the context of the disclosure, the term “subject”generally refers to an individual who will receive or who has receivedtreatment described below (e.g., administration of the compounds of thedisclosure, and optionally one or more additional therapeutic agents).

Where substituent groups are specified by their conventional chemicalformula, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedchain, or cyclic hydrocarbon radical, or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclopropyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. Alkyl groups which are limited tohydrocarbon groups are termed “homoalkyl”.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkyl, as exemplified, but not limited,by —CH₂CH₂CH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CCCH₂—, —CH₂CH₂CH(CH₂CH₂CH₃)CH₂—.Typically, an alkyl (or alkylene) group will have from 1 to 24 carbonatoms. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl oralkylene group, generally having eight or fewer carbon atoms. The term“heteroalkyl,” by itself or in combination with another term, means,unless otherwise stated, a stable straight or branched chain, or cyclichydrocarbon radical, or combinations thereof, consisting of at least onecarbon atoms and at least one heteroatom selected from the groupconsisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus,and sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N, P and S and Simay be placed at any interior position of the heteroalkyl group or atthe position at which alkyl group is attached to the remainder of themolecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. Similarly, the term “heteroalkylene” by itself or aspart of another substituent means a divalent radical derived fromheteroalkyl, as exemplified, but not limited by, —CH₂—CH₂—S—CH₂—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxo,alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —C(O)OR′—represents both —C(O)OR′— and —R′OC(O)—. As described above, heteroalkylgroups, as used herein, include those groups that are attached to theremainder of the molecule through a heteroatom, such as —C(O)R′,—C(O)NR′, —NR′R″, —OR′, —SR, and/or —SOO₂R′. Where “heteroalkyl” isrecited, followed by recitations of specific heteroalkyl groups, such as—NR′R″ or the like, it will be understood that the terms heteroalkyl and—NR′R″ are not redundant or mutually exclusive. Rather, the specificheteroalkyl groups are recited to add clarity. Thus, the term“heteroalkyl” should not be interpreted herein as excluding specificheteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclopropyl,cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.Examples of heterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. The terms “cycloalkylene”and “heterocycloalkylene” refer to the divalent derivatives ofcycloalkyl and heterocycloalkyl, respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent which can be a single ring or multiplerings, which are fused together or linked covalently. The term“heteroaryl” refers to aryl groups (or rings) that contain from one tofour heteroatoms (in each separate ring in the case of multiple rings)selected from N, O, and S, wherein the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a carbon or heteroatom. Non-limiting examples of aryland heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of above noted aryland heteroaryl ring systems are selected from the group of acceptablesubstituents described below. The terms “arylene” and “heteroarylene”refer to the divalent radicals of aryl and heteroaryl, respectively.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxo, arylthioxo, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like). However, theterm “haloaryl,” as used herein is meant to cover only aryls substitutedwith one or more halogens.

Where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specificnumber of members (e.g., “3 to 7 membered”), the term “member” refers toa carbon or heteroatom.

The term “oxo or keto” as used herein means an oxygen that is doublebonded to a carbon atom.

The terms “heterocycle” and “heterocyclic” refer to a monovalentunsaturated group having a single ring or multiple condensed rings, from1 to 8 carbon atoms and from 1 to 4 heteroatoms, for example, nitrogen,sulfur or oxygen within the ring.

The term “methylthio” refers to a moiety —S—CH₃. Sulfonyl refers toS-oxide.

The term “sulfonamide” refers to compound A shown below, as well as tothe other

R—SO₂—N—R₂  A

moieties derived from compound A: The terms “furyl,” “tetrahydrofuryl,”and “pyridyl” refer to radicals formed by removing one hydrogen from themolecules of furan, tetrahydrofuran, and pyridine, respectively.

The terms “alkyl amine” and “cyclic amine” refer to alkanes orcycloalkanes, respectively, having one hydrogen substituted by aprimary, secondary or tertiary amino group, as well as to the moietiesand radicals derived from such amines.

The term “alkyl amide” refers to alkanes, having one hydrogensubstituted by a primary, secondary or tertiary amino group.

Each of above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl, and“heterocycloalkyl”, “aryl,” “heteroaryl” as well as their divalentradical derivatives) are meant to include both substituted andunsubstituted forms of the indicated radical.

Substituents for alkyl, heteroalkyl, cycloalkyl, heterocycloalkylmonovalent and divalent derivative radicals (including those groupsoften referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —C(O)NR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)OR′,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number ranging from zero to (2m′+1), where m′ is the totalnumber of carbon atoms in such radical. R′, R″, R′″ and R″″ eachindependently refer to hydrogen, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g.,aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl,alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of thedisclosure includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5, 6-, or 7-membered ring. For example,—NR′R″ is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O) CF₃, —C(O) CH₂O CH₃, and the like).

The term “alkoxy” refers to the moiety —O-alkyl, wherein alkyl is asdefined above. Examples of alkoxy structures that are within the purviewof the definition include, but are not limited to, (C₁-C₆)alkoxyradicals, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, 3-pentoxy, or hexyloxy.

Similar to the substituents described for alkyl radicals above,exemplary substituents for aryl and heteroaryl groups (as well as theirdivalent derivatives) are varied and are selected from, for example:halogen, —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′,—CO₂R′, —C(O)NR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR″C(O)OR′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR SO₂R′, —CN and —NO₂, —R′, —N₃, —CH(Ph)₂,fluoro(C₁-C₄)alkoxo, and fluoro(C₁-C₄)alkyl, in a number ranging fromzero to the total number of open valences on aromatic ring system; andwhere R′, R″, R′″ and R″″ are independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. When a compound of thedisclosure includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present.

Two of the substituents on adjacent atoms of aryl or heteroaryl ring mayoptionally form a ring of the formula -T-C(O)—(CRR′)q-U—, wherein T andU are independently —NR—, —O—, —CRR′— or a single bond, and q is aninteger of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)r-B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″ and R′″ are independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

As used herein, the term “heteroatom” or “ring heteroatom” is meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), or silicon(Si).

An “aminoalkyl” as used herein refers to an amino group covalently boundto an alkylene linker. The amino group is —NR′R″, wherein R′ and R″ aretypically selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

A “substituent group,” as used herein, means a group selected from thefollowing moieties: (A) —OH, —NH₂, —SH, —CN, —CF₃, —NO₂, —S(O)-alkyl,—S(O)-aryl, —S(O₂)-alkyl, S(O₂)-aryl, oxo, halogen, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B)alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,substituted with at least one substituent selected from: (i) oxo, —OH,—NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, unsubstituted heteroaryl, and (ii) alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,substituted with at least one substituent selected from: (a) oxo, —OH,—NH₂, —SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,substituted with at least one substituent selected from oxo, —OH, —NH₂,—SH, —CN, —CF₃, —NO₂, halogen, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, and unsubstituted heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₄-C₈cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl.

A “lower substituent” or “lower substituent group,” as used herein meansa group selected from all of the substituents described above for a“substituent group,” wherein each substituted or unsubstituted alkyl isa substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₅-C₇ cycloalkyl, and each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7membered heterocycloalkyl.

In the examples, we categorized the effects of 1 on biological assays asfollows: ++++, IC₅₀ 0-10 μM; +++, IC₅₀ 10-50 μM; ++, IC₅₀ 50-100 μM; +,IC₅₀>100 μM; NR, no response.

The compounds of the disclosure may exist as salts. Examples ofapplicable salt forms include hydrochlorides, hydrobromides, sulfates,methanesulfonates, nitrates, maleates, acetates, citrates, fumarates,tartrates (e.g., (+)-tartrates, (−)-tartrates or mixtures thereofincluding racemic mixtures, succinates, benzoates and salts with aminoacids such as glutamic acid. These salts may be prepared by methodsknown to those skilled in art. Also included are base addition saltssuch as sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When the disclosed compounds containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of acceptable acid addition salts include those derived frominorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived organicacids like acetic, propionic, isobutyric, maleic, malonic, benzoic,succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike. Certain specific compounds of the disclosure contain both basicand acidic functionalities that allow the compounds to be converted intoeither base or acid addition salts.

The term “pharmaceutically acceptable salts” is meant to include saltsof active compounds which are prepared with relatively nontoxic acids orbases, depending on the particular substituent moieties found on thecompounds described herein. When compounds of the disclosure containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds of the disclosure contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977,66, 1-19). Certain specific compounds of the disclosure contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents.

Certain compounds of the disclosure can exist in unsolvated forms aswell as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the disclosure. Certain compounds of the disclosuremay exist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated by and areintended to be within the scope of the disclosure.

Certain compounds of the disclosure possess centers of chirality (e.g.,asymmetric carbon atoms), optical or chiral centers or double bonds; theenantiomers, racemates, diastereomers, tautomers, geometric isomers,stereoisometric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids,and individual isomers are encompassed within the scope of thedisclosure. The compounds of the disclosure do not include those whichare known in art to be too unstable to synthesize and/or isolate. Thedisclosure is meant to include compounds in racemic and optically pureforms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another. It will be apparent to oneskilled in the art that certain compounds of the disclosure may exist intautomeric forms, all such tautomeric forms of the compounds beingwithin the scope of the disclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each center of chirality (e.g., an asymmetric carboncenter). Therefore, single stereochemical isomers as well asenantiomeric and diastereomeric mixtures of the present compounds arewithin the scope of the disclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of the disclosure.

The compounds of the disclosure may also contain unnatural proportionsof atomic isotopes at one or more atoms that constitute such compounds.For example, the compounds may be radiolabeled with radioactive isotope,such as for example, tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C).All isotopic variations of the compounds of the disclosure, whetherradioactive or not, are encompassed within the scope of the disclosure.Nonradioactive isotopes include deuterium (²H), carbon-13 (¹³C) andnitrogen-15 (¹⁵N).

In addition to salt forms, the disclosure provides compounds, which arein a prodrug form. Prodrugs of the compounds described herein are thosecompounds that readily undergo chemical or metabolism-mediated changesunder physiological conditions to provide the compounds of thedisclosure. For example, a phosphate or other ester moiety or otherprodrug moiety may be independently attached to R₁-R₆). Additionally,prodrugs can be converted to the compounds of the disclosure by chemicalor biochemical methods in an ex vivo environment. For example, prodrugscan be slowly converted to the compounds of the disclosure when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent.

The terms “a,” “an,” or “a(n)”, when used in reference to a group ofsubstituents herein, mean at least one. For example, where a compound issubstituted with “an” alkyl or aryl, the compound is optionallysubstituted with at least one alkyl and/or at least one aryl. Moreover,where a moiety is substituted with an R substituent, the group may bereferred to as “R-substituted.” Where a moiety is R-substituted, themoiety is substituted with at least one R substituent and each Rsubstituent is optionally different.

Description of compounds of the disclosure are limited by principles ofchemical bonding known to those skilled in the art. Accordingly, where agroup may be substituted by one or more of a number of substituents,such substitutions are selected so as to comply with principles ofchemical bonding and to give compounds which are not inherently unstableand/or would be known to one of ordinary skill in the art as likely tobe unstable under ambient conditions, such as aqueous, neutral, andseveral known physiological conditions. For example, a heterocycloalkylor heteroaryl is attached to the remainder of the molecule via a ringheteroatom in compliance with principles of chemical bonding known tothose skilled in the art thereby avoiding inherently unstable compounds.

The terms “treating” or “treatment” in reference to a particular diseaseincludes prevention of the disease.

The disclosure also provides articles of manufacture comprisingpackaging material and a pharmaceutical composition contained withinsaid packaging material, wherein said packaging material comprises alabel which indicates that said pharmaceutical composition can be usedfor treatment of disorders and wherein said pharmaceutical compositioncomprises a compound according to the disclosure.

The disclosure also provides pharmaceutical compositions comprising atleast one compound in an amount effective for treating a disorder, and apharmaceutically acceptable vehicle or diluent. The compositions of thedisclosure may contain other therapeutic agents as described below, andmay be formulated, for example, by employing conventional solid orliquid vehicles or diluents, as well as pharmaceutical additives of atype appropriate to the mode of desired administration (for example,excipients, binders, preservatives, stabilizers, flavors, etc.)according to techniques such as those well known in the art ofpharmaceutical formulation.

The compounds of the disclosure may be formulated into therapeuticcompositions as natural or salt forms. Pharmaceutically acceptablenon-toxic salts include the base addition salts (formed with freecarboxyl or other anionic groups) which may be derived from inorganicbases such as, for example, sodium, potassium, ammonium, calcium, orferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like.Such salts may also be formed as acid addition salts with any freecationic groups and will generally be formed with inorganic acids suchas, for example, hydrochloric, sulfuric, or phosphoric acids, or organicacids such as acetic, citric, p-toluenesulfonic, methanesulfonic acid,oxalic, tartaric, mandelic, and the like. Salts of the disclosureinclude amine salts formed by the protonation of an amino group withinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, phosphoric acid, and the like. Salts of thedisclosure may also include amine salts formed by the protonation of anamino group with suitable organic acids, such as p-toluenesulfonic acid,acetic acid, and the like. Additional excipients which are contemplatedfor use in the practice of the disclosure are those available to thoseof ordinary skill in the art, for example, those found in the UnitedStates Pharmacopeia Vol. XXII and National Formulary Vol. XVII, U.S.Pharmacopeia Convention, Inc., Rockville, Md. (1989), the relevantcontents of which is incorporated herein by reference. In addition,polymorphs, hydrates, and solvates of the compounds are included in thedisclosure.

The disclosed pharmaceutical compositions may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; buccally; parenterally,such as by subcutaneous, intravenous, intramuscular, intrathecal, orintracisternal injection or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasallysuch as by inhalation spray; topically, such as in the form of a creamor ointment; or rectally such as in the form of suppositories; in dosageunit formulations containing non-toxic, pharmaceutically acceptablevehicles or diluents. The present compounds may, for example, beadministered in a form suitable for immediate release or extendedrelease. Immediate release or extended release may be achieved by theuse of suitable pharmaceutical compositions comprising the presentcompounds, or, particularly in the case of extended release, by the useof devices such as subcutaneous implants or osmotic pumps. The presentcompounds may also be administered liposomally or with cavitands (i.e.,Captisol).

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the disclosure. For instance,mammals including, but not limited to, cows, sheep, goats, horses, dogs,cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline,rodent or murine species can be treated. However, the method can also bepracticed in other species, such as avian species (e.g., chickens).

The term “therapeutically effective amount” means the amount of thecompound or pharmaceutical composition that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, e.g., restoration or maintenance of vasculostasis orprevention of the compromise or loss or vasculostasis; reduction oftumor burden; reduction of morbidity and/or mortality.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the disclosure orpharmaceutical composition to the subject in need of treatment. The term“contacting” should be understood to mean providing a compound of thedisclosure or pharmaceutical composition either in vitro or in vivo.

The pharmaceutical compositions for the administration of the compoundsof this embodiment either alone or in combination with other agents, mayconveniently be presented in dosage unit form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing the active ingredient into association with thecarrier which constitutes one or more accessory ingredients. In general,the pharmaceutical compositions are prepared by uniformly and intimatelybringing the active ingredient into association with a liquid carrier ora finely divided solid carrier or both, and then, if necessary, shapingthe product into the desired formulation. In the pharmaceuticalcomposition the active object compound is included in an amountsufficient to produce the desired effect upon the process or conditionof disease. The pharmaceutical compositions containing the activeingredient may be in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.Also useful as a solubilizer is polyethylene glycol, for example. Theaqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a parenterally-acceptable diluent or solventor cosolvent or complexing agent or dispersing agent or excipient orcombination thereof, for example 1,3-butane diol, polyethylene glycols,polypropylene glycols, ethanol or other alcohols, povidones, Tweens,sodium dodecyle sulfate, sodium deoxycholate, dimethylacetamide,polysorbates, poloxamers, cyclodextrins, e.g., sulfobutyl etherO-cyclodextrin, Captisol, lipids, and excipients such as inorganic salts(e.g., sodium chloride), buffering agents (e.g., sodium citrate, sodiumphosphate), and sugars (e.g., saccharose and dextrose). Among theacceptable vehicles and solvents that may be employed are water,dextrose solutions, Ringer's solutions and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Depending on the condition being treated, these pharmaceuticalcompositions may be formulated and administered systemically or locally.Suitable routes may, for example, include oral or transmucosaladministration; as well as parenteral delivery, including intramuscular,subcutaneous, intramedullary, intrathecal, intraventricular,intravenous, intraperitoneal, or intranasal administration. Forinjection, the pharmaceutical compositions of the disclosure may beformulated in aqueous solutions, for example, in physiologicallycompatible buffers such as Hanks' solution, Ringer's solution, orphysiologically buffered saline. For tissue or cellular administration,penetrants appropriate to the particular barrier to be permeated areused in the formulation. Such penetrants are generally known in the art.Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

The compounds of the disclosure may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols. Fortopical use, creams, ointments, jellies, solutions or suspensions, etc.,containing the compounds of the disclosure are employed. For purposes ofthis application, topical application shall include mouthwashes andgargles.

In the methods described herein, an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per daywhich can be administered in single or multiple doses. The dosage levelcan be about 0.01 to about 250 mg/kg per day, such as 0.01 to about 100mg/kg per day, for example, 0.01 to about 10 mg/kg per day, such as 0.04to about 5 mg/kg per day, or about 0.5 to about 100 mg/kg per day. Asuitable dosage level may be also about 0.05 to 100 mg/kg per day, orabout 0.1 to 50 mg/kg per day or 1.0 mg/kg per day. Within this rangethe dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day forexample. The Examples section shows that one of the exemplary compoundswas dosed at 30 mg/kg/day and also at about 100 mg/kg/day. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, or once or twice perday. There may be a period of no administration followed by anotherregimen of administration. Administration of the compounds may beclosely associated with the schedule of a second agent ofadministration.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the potency of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, gender, diet, mode andtime of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

Thus, in one embodiment the disclosure provides a compound of Formula Ior stereoisomers or a pharmaceutically acceptable salt, prodrugs,N-oxide or solvate capable of inhibiting sodium channels:

Formula I

A, B, D are independently Carbon, Nitrogen. R, R₁, R₂, R₃, R₄, R₅═H,deuterium, alkyl, aryl, halo, O-alkyl, O-aryl, N-alkyl, N,N-dialkyl,N-aryl, N,N-diaryl, S-, S-aryl, S(O)-alkyl, S(O)-aryl, S(O₂)-alkyl,S(O₂)-aryl, cycloalkyl, cycloheteroalkyl, heteroaryl.

R is independently substituted hydrogen, deuterium, trideuteromethyl,(C₁-C₆)alkyl, aryl, halogen, CF₃, C₂F₅, O-alkyl, N-alkyl, O-aryl,—(CH₂)₁₋₆OH, —(CH₂)₁₋₆SH, —(CH₂)₁₋₆NH₂, —(CH₂)₁₋₆OR₁₁, —(CH₂)₁₋₆SR₁₁,—(CH₂)₁₋₆N(R₁₁)₂. where R₁₁ is independently substituted hydrogen,(C₁-C₆)alkyl, aryl, CF₃, C₂F₅, hydroxyl, O-alkyl, O-aryl,cycloalkyl(C₁-C₆), alkyl(C₁-C₆)amine, alkyl cyclic(C₁-C₆)amine,alkyl(C₁-C₆) N,N-dialkylamino, alkyl (C₁-C₆)aryl amine,cycloheteroalkyl, heteroaryl, methylcycloalkyl(C₁-C₆), methylaryl,methylcycloheteroalkyl, methylheteroaryl, methylcyclopropyl, or a moietyforming a salt; or unsubstituted phenyl, substituted or unsubstitutedpyridine, wherein phenyl or pyridine is optionally independentlysubstituted with 1 to 3 independently substituted; or a moiety forming asalt;

R₁ is independently substituted hydrogen, deuterium, trideuteromethyl,(C₁-C₆)alkyl, aryl, halogen, CF₃, C₂F₅, O-alkyl, N-alkyl O-aryl,—(CH₂)₁₋₆OH, —(CH₂)₁₋₆SH, —(CH₂)₁₋₆NH₂, —(CH₂)₁₋₆OR₁₁, —(CH₂)₁₋₆SR₁₁,—(CH₂)₁₋₆N(R₁₁)₂. where R₁₁ is independently substituted hydrogen,(C₁-C₆)alkyl, aryl, CF₃, C₂F₅, hydroxyl, O-alkyl, O-aryl,cycloalkyl(C₁-C₆), alkyl(C₁-C₆)amine, alkyl cyclic(C₁-C₆)amine,alkyl(C₁-C₆) N,N-dialkylamino, alkyl (C₁-C₆)aryl amine,cycloheteroalkyl, heteroaryl, methylcycloalkyl(C₁-C₆), methylaryl,methylcycloheteroalkyl, methylheteroaryl, methylcyclopropyl, or a moietyforming a salt; or unsubstituted phenyl, substituted or unsubstitutedpyridine, wherein phenyl or pyridine is optionally independentlysubstituted with 1 to 3 independently substituted; or a moiety forming asalt;

R₂ is independently substituted hydrogen, deuterium, trideuteromethyl,O, O₂, (C₁-C₆)alkyl, aryl, CF₃, C₂F₅, hydroxyl, O-alkyl, O-aryl,cycloalkyl(C₁-C₆), alkyl(C₁-C₆)amine, alkyl cyclic(C₁-C₆)amine,alkyl(C₁-C₆) N,N-dialkylamino, alkyl (C₁-C₆)aryl amine,cycloheteroalkyl, heteroaryl, methylcycloalkyl(C₁-C₆), methylaryl,methylcycloheteroalkyl, methylheteroaryl, methylcyclopropyl, or a moietyforming a salt; or unsubstituted phenyl, substituted or unsubstitutedpyridine, wherein phenyl or pyridine is optionally independentlysubstituted with 1 to 3 independently substituted;

R₃ is independently substituted hydrogen, deuterium, trideuteromethyl,(C₁-C₆)alkyl, aryl, halogen, CF₃, C₂F₅, O-alkyl, O-aryl, S-alkyl,S-aryl, amine, cyclic amine, aryl amine or a moiety forming a salt;

R₄ is independently substituted hydrogen, deuterium, trideuteromethyl,(C₁-C₆)alkyl, aryl, halogen, CF₃, C₂F₅, O-alkyl, O-aryl, S-alkyl,S-aryl, S(O)-alkyl, S(O)-aryl, S(O₂)-alkyl, S(O₂)-aryl, amine, cyclicamine, aryl amine or a moiety forming a salt;

R₅ is independently substituted hydrogen, deuterium, (C₁-C₆)alkyl, aryl,halogen, CF₃, C₂F₅, hydroxyl, O-alkyl, O-aryl, S-alkyl, S-aryl,S(O)-alkyl, S(O)-aryl, S(O₂)-alkyl, S(O₂)-aryl, cycloalkyl(C₁-C₆),alkyl(C₁-C₆)amine, alkyl cyclic(C₁-C₆)amine, alkyl(C₁-C₆)N,N-dialkylamino, alkyl (C₁-C₆)aryl amine, cycloheteroalkyl, heteroaryl,methylcycloalkyl(C₁-C₆), methylaryl, methylcycloheteroalkyl,methylheteroaryl, methylcyclopropyl, or a moiety forming a salt; orunsubstituted phenyl, substituted or unsubstituted pyridine, whereinphenyl or pyridine is optionally independently substituted with 1 to 3independent substitutes, O-alkyl, O-aryl, amino, N-alkylamino,N-arylamino, or hydroxyl or amino prodrug moieties;

R₆ is independently substituted hydrogen, deuterium, trideuteromethyl,(C₁-C₆)alkyl, aryl, halogen, CF₃, C₂F₅, O-alkyl, N-alkyl O-aryl,—(CH₂)₁₋₆OH, —(CH₂)₁₋₆SH, —(CH₂)₁₋₆NH₂, —(CH₂)₁₋₆OR₁₁, —(CH₂)₁₋₆SR₁₁,—(CH₂)₁₋₆N(R₁₁)₂. where R₁₁ is independently substituted hydrogen,(C₁-C₆)alkyl, aryl, CF₃, C₂F₅, hydroxyl, O-alkyl, O-aryl,cycloalkyl(C₁-C₆), alkyl(C₁-C₆)amine, alkyl cyclic(C₁-C₆)amine,alkyl(C₁-C₆) N,N-dialkylamino, alkyl (C₁-C₆)aryl amine,cycloheteroalkyl, heteroaryl, methylcycloalkyl(C₁-C₆), methylaryl,methylcycloheteroalkyl, methylheteroaryl, methylcyclopropyl, or a moietyforming a salt; or unsubstituted phenyl, substituted or unsubstitutedpyridine, wherein phenyl or pyridine is optionally independentlysubstituted with 1 to 3 independently substituted; or a moiety forming asalt;

R is independently substituted S and/or R isomeric forms and/or racemicforms,

In another aspect the disclosure provides methods for stereoselectivelysynthesizing compounds inhibiting sodium channels, comprising contactingcells with a aryloxy propan-2-amine-based compound of Formula I in theform of a free base or a pharmaceutically acceptable salt, prodrug,hydrate, solvate or N-oxide thereof, wherein A, B, D, R, R₁-R₆, are asdescribed above.

In another aspect the disclosure provides methods for stereoselectivelyinhibiting sodium channels, comprising contacting cells with a aryloxypropan-2-amine-based compound of Formula I in the form of a free base ora pharmaceutically acceptable salt, prodrug, hydrate, solvate or N-oxidethereof, wherein A, B, D, R, R₁-R₆, are as described above.

R is independently substituted as the R isomeric form

R is independently substituted S and/or R isomeric forms and/or racemicforms,

In another aspect the disclosure provides compounds of Formula I whereinthe pharmaceutically acceptable salt is the salt of1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoicacid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid(L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoricacid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid),caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconicacid (D), glucuronic acid (D), glutamic acid, glutaric acid,glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid,lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid(DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid,oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionicacid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearicacid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid,toluenesulfonic acid (p), or undecylenic acid

EXAMPLES

The embodiments of the disclosure may be further illustrated by thefollowing non-limiting examples.

Example 1: Kinetics for APD in Cardiomyocytes

Data (i.e., IC50 values) from experiments with normal human inducedpluripotent stem cell (hiPSC) cardiomyocyte or cardiomyocytes derivedfrom hiPSCs from a LQTS3 patient (cells obtained from CDI International)were obtained from dose escalation experiments using a high throughputmembrane potential assay using the novel voltage sensitive dye, VF2.1Cl. Normal or LQTS3 patient-derived cardiomyocytes were cultured for 2weeks prior to imaging. On the day of the experiment, the cells werewashed with Tyrode's solution and each compound was added to the cellsfrom a 2× stock, incubated for 5 minutes and imaged for 6.5 seconds at100 Hz using a kinetic imaging cytometer (KIC) (Vala Sciences) to obtainfluorescence versus concentration effects. Subsequent image analysis andphysiological parameter calculations was conducted using Cyteseersoftware from Vala Sciences. Dose response curves were generated usingGraphpad Prism software. Maturity of sodium, potassium and calciumchannels were fully characterized in both normal and LQT3 cardiomyocyteswith single cell patch clamp voltage-gated studies. This data wascompared to data obtained from channels transfected into cells (seeExample 2).

Normal cardiomyocytes dose response. A plot of log of action potentialdelay (APD)75 vs. log of racemic Mexiletine or Mexiletine analogsconcentration in molar dose response curve for a dose escalation ofMexiletine in normal hiPSC derived cardiomyocytes afforded prolongationof 2.85 fold (n=5) (Table 1, below). The plot showed the dose dependentprolongation of the action potential duration in response to Mexiletine.

LQTS3 dose response-log: A plot of log of APD75 vs. log of racemicMexiletine concentration in molar dose response curve for a doseescalation of Mexiletine in LQTS3 patient-derived cardiomyocytesafforded an IC50 value of 1.83 uM for shortening APD and 1.34-foldshortening (n=5) (Table 2, below). The plot showed a dose dependentshortening of the action potential duration for a dose escalation ofMexiletine. The data showed the utility of using normal human andpatient-derived cardiomyocytes to afford molecules with superioron-target vs. off-target effects. Mexiletine analogs were likewisetested. This identified optimal compounds that shortened the APD.

TABLE 1 Pharmacological Parameters in Normal human IPSC-derivedCardiomyocytes. Peak Late hER WT- WT- Cess- Na⁺ Na⁺ G WT- Fold Prolong-ation (I_(NaP)) (I_(NaL)) (I_(Kr)) EAD Pro- ation of No. IC₅₀ IC₅₀D_(Nap/) IC₅₀ D_(Kr/) D_(NaP/) Dose long- Dose Beating Code Structure(uM) (uM) _(NaL) (uM) _(NaL/) _(Kr) (uM) ation (uM) (uM) 1

183 22 8.3 54 2.5 3.4 200 2.653 66 2a

128 30 4.3 54 1.8 2.4 200 2.661 133 2b

129 19 6.8 84 4.4 1.5 200 2.289 200 9

162 52 3.1 98 1.9 1.7 200 2.363 200 10

130 7.3 18.0 30 4.1 4.3 66 2.262 22 11

124 36 3.4 44 1.2 2.8 22 2.194 22 12

91 11 8.3 49 4.5 1.9 7.4 >4 22 13

21 12 1.8 8 0.7 2.6 1.389 22 14

None None None 15

None None 66 16

None None 66 17

None None 66 18

None None None 19

None None 133 20

None None None 21

128.6 21.2 6.1 100 4.7 1.3 None None None 22

Not Done 23

None None 22 24

None None 66 25

34.2 0.642 53.3 22.9 35.7 1.5 None None 133 26

7.4 2.502 7.4 22 27

41.1 1.04 39.5 37.5 36.1 1.1 None None 66 28

None None 66 29

None None None 30

None None 133 31

None None None 32

None None 133 33

None None 133 34

None None 133 35

None None 133 36

25.8 0.747 34.5 27.6 36.9 0.9 None None None 37

None None None 38

66 4.584 66 200 39

66 3.827 22 133 40

66 4.366 32 None 41

133 5.338 32 None 42

1.684 5.7 200 43

None None None 44

22 2.698 2.5 133 45

None None None 46

None None None 47

Not Determined 48

None None None 49

1.385 7.8 200 50

1.392 23.5 None 51

None None None 52

133 2.499 97.7 None 53

None None None 54

None None 66 55

154 17 9.1 49 2.9 3.1 1.159 22 None 56

133 3.925 133 None 57

200 3.615 133 None 58

200 2.392 133 None 59

133 2.832 22 None 60

66 2.805 22 200 61

66 3.829 66 None 62

66 1.585 66 200 63

66 1.577 66 None 64

133 2.621 66 None 65

66 2.12 66 200 66

22.1 2.1 10.5 5.9 2.8 3.7 None None 66 67

135.6 10.6 12.8 63 5.9 2.2 66 2.408 66 None 68

66 1.686 66 200 69

38.3 0.845 45.3 5.1 6.0 7.5 None None 200 70

18.9 0.182 103 6.2 34.0 3.0 None None 66 71

200 1.997 200 None 72

133 2.93 200 None 73

None None 66 74

133 2.633 133 None 75

None None 66 76

None None 66 77

None None 66 78

20 1.03 19.4 None None 133 79

200 5.06 133 None 80

45.1 1.02 44.2 16.8 16.5 2.7 None None None 81

None None 66 82

44.3 1.14 38.9 None None 66 83

None None 133 84

None None 133 85

None None 200 86

66 1.68 66 None 87

None None None 88

1.52 66 None 89

24.3 1.6 15.2 4.9 3.1 5.0 90

33.4 2.83 11.8 None None 133 91

76.8 10 7.7 45.8 4.6 1.7 92

None None 66 93

None None 66 94

133 2.48 133 None 95

133 2.68 200 None 96

1.163 200 None 97

133 None None None 98

1.54 7.4 99

100

252 n/a n/a n/a n/a n/a None None None No. LQT-IC50 (uM)- LQT-CessationLQT-EAD LQT-Fold LQT-Shortening Code Structure Shortening Dose (uM) Dose(uM) Shortening Dose (uM) 1

1.83 None 1.335 22 2a

0.96 None 1.346 7.4 2b

0.8 None 1.25 22 9

0.76 None 1.28 22 10

0.8 200 1.162 22 11

1.48 133 1.112 22 12

0.648 22 1.182 2.5 13

0.72 66 1.174 2.5 14

None None None None 15

66 1.42 7.4 16

1.38 66 1.480 22 17

66 1.58 22 18

None None None 19

1.38 133 1.406 66 20

None None None 21

None 1.23 7.4 22

None 1.29 133 23

0.78 22 1.32 2.5 24

0.38 22 1.979 7.4 25

0.73 66 1.606 22 26

0.13 133 1.482 0.8 27

>0.8 66 1.783 22 28

>0.8 66 1.620 22 29

>0.8 None 1.64 66 30

20.16 200 1.423 133 31

133 None None 32

7.53 66 1.355 22 33

22 None None 34

66 1.29 22 35

66 1.406 22 36

5.73 200 1.508 133 37

None None None 38

200 1.19 2.5 39

0.73 66 1.180 2.5 40

2.31 None 1.267 7.4 41

None None None 42

133 1.26 22 43

None None None 44

7.4 1.7 2.5 45

None 1.37 133 46

None 1.67 133 47

Not done — — 48

None None None 49

0.85 133 1.192 7.4 50

6.01 None 1.12 22 51

None 1.37 133 52

None None None 53

None None None 54

57.82 133 1.45 66 55

4.45 200 1.232 66 56

0.04 None 1.189 7.4 57

0.19 None 1.14 7.4 58

None None None 59

None None None 60

0.11 200 1.22 0.8 61

200 None None 62

1.03 200 1.19 22 63

7.5 200 1.11 22 64

None None None 65

1.36 200 1.119 66 66

0.486 66 1.192 7.4 67

None None None None 68

0.022 200 1.11 66 69

None 200 None None 70

0.0013 66 1.279 7.4 71

193.7 (prolongation) None  1.214 (prolongation) 200 72

128.9 (prolongation) None  1.133 (prolongation) 200 73

0.082 66 1.136 0.8 74

None None None 75

66 1.370 22 76

66 1.244 22 77

200 1.18 22 78

23.08 66 1.208 22 79

None 1.145 133 80

6.59 133 1.636 66 81

4.07 66 1.539 22 82

20.56 66 1.442 22 83

0.0023 66 1.410 22 84

0.87 66 1.200 7.4 85

31.34 200 1.661 133 86

Shortens None 1.418 200 87

34.78 None 1.611 133 88

12.82 None 1.287 66 89

90

133 1.1 22 91

92

66 1.41 22 93

22 1.5 7.4 94

None None None 95

22 1.22 22 96

None 1.3 133 97

None 1.1 22 98

66 1.3 22 99

22 1.49 7.4 100

22 1.13 7.4

Example 2. Electrophysiology

INa and IKr assays (n=6) were run by patch clamp electrophysiology andconfirmed the in vitro potency observed with the Kinetic Image Cytometer(KIC) assays. This provided data to investigate the physiology andaction of target compounds on individual ion channels. The assay usedstandardized protocols for culturing and conducting conventional wholecell recording that have been previously developed for both current andvoltage-clamp to characterize action potentials using transfected cells.Briefly, the Nav1.5 sodium channel was transfected into HEK293 cells.The cells were validated using standard assays previously developed andfurther validated using dose response studies that afforded IC50 values.hERG was expressed in CHO cells and used in automated patch clampassays. Briefly, cells were plated on 0.1% gelatin-coated 35-mm plasticPetri dishes. Conventional whole cell recording conditions were used inboth current and voltage-clamp to characterize action potentials inthese cells to investigate the physiology and pharmacology of individualion channels and the effect of Mexiletine or Mexiletine analogs onfunction. Data was reported as IC₅₀ values±STD (Table 1). For example,racemic Mexiletine had NaI channel Peak (INaP) IC₅₀=183 μM, NaI channelLate (INaL) IC₅₀=22 μM (ratio=8.3) and hERG potassium channel (IKr)IC₅₀=54 VM. Compound 70 had a Na Peak IC₅₀=18.9 VM, Na Late IC₅₀=0.18 μM(ratio=104) and hERG IC₅₀=6 PIM. Analog 70 was thus much more selectivefor the on-target Na Late channel than Mexiletine.

TABLE 1 Electrophysiology Results for Mexiletine and Analogs usingTransfected Cells. Results Peak Na⁺ Late Na⁺ hERG (I_(NaP)) IC₅₀(I_(NaL)) IC₅₀ (I_(Kr)) IC₅₀ Compound Structure (μM) (μM) D_(NaP)/_(NaL)(μM) D_(Kr)/_(NaL) D_(NaP)/_(Kr) Rac 182.8 22.5 8.3 54 2.5 73Mexiletine,  1  36

25.8 0.747 34.5 27.6 36.9 0.93  70

20.1 0.2 100.5 6.2 34.0 3.0  91

76.8 10.0 7.68 45.8 4.6 1.7  21

128.6 21.2 6.1 >100 >4.7 1.3  69

38.0 0.753 50.5 5.1 6.8 7.5  67

135.6 10.6 12.8 63.0 5.9 2.2  25

34.2 0.642 53.2 22.9 35.6 1.5  82

41.1 1.04 39.5 37.5 36.1 1.1  89

24.3 1.6 15.3 4.9 3.1 5.0  66

22.1 2.1 10.7 5.9 2.8 3.7  78

20.0 1.03 19.4 7.2 7.0 2.77  80

45.1 1.02 44.2 16.8 16.5 2.7  88

90.9 1.04 87.4 11.2 10.7 7.7 105

44.3 1.14 38.9 20.9 18.3 2.11  90

33.4 2.83 11.8 25.3 1.32 1.32  35

10.9 1.03 10.6 9.2 8.9 1.2

Patch clamp recordings from hIPSC LQT3 patient-derived cardiomyocytesfor Na+ channel currents were recorded in response to computed voltagewaveforms that simulated adult ventricular action potentials. Thesechannels were recorded in human cardiomyocytes and showed all therelevant ion channels in a native context. This confirmed the KIC datathat revealed a compound's on- and off-target effects. Patch-clamprecording of hIPSC-LQT3 patient-derived cardiomyocytes showed thepresence of functional K+, Na+ and Ca2+ currents, typical for functionalcardiomyocytes. Patch clamp studies with LQT3 patient-derivedcardiomyocytes showed a significantly prolonged Na+ current, reflectingthe substantial proportion of late Na+ current component. The NaIchannel Peak (INaP) IC50>100 μM, NaI channel Late (INaL) IC50=1.8 μM(ratio >56) for 82. The NaI channel Peak (INaP) IC50>100 μM, NaI channelLate (INaL) IC50=1.74 μM (ratio>57) for 25. The results are in goodagreement with previous electrophysiology data (Table 1, above) and thatobtained from optical screening assays (KIC assays). The results showedmore potent and selective sodium channel inhibitors with more favorable(lower) potassium channel inhibition were obtained.

Example 3: Synthesis of Compounds of Formula I

The phenoxy propan-2-amine-based compounds of general structure I:

was synthesized according to the following Schemes:

Potassium carbonate (1.5 eq.) was added to a stirred solution of2,6-dimethylphenol (1.5 eq.) and bromoacetone (0.5 M, 1.0 eq.) in DMF at21° C. After 12-24 hours, the mixture was poured into water andextracted with diethyl ether (2×), washed with 2N NaOH_((aq)) (5×),dried (Na₂SO₄), filtered, and concentrated. The product was purified bysilica gel column chromatography (ethyl acetate/hexanes) to providealpha-aryloxy ketones.

The synthesis of Mexiletine enantiomers was done as follows. A two-stepcondensation-reduction protocol was used to convert ketones 5 toN-tert-butanesulfinyl amines 7 without isolation of hydrolyticallyunstable N-tert-butanesulfinyl imines (i.e., 6). Reduction of 6 showedsubstrate and reagent-based stereoselectivity wherein sodium borohydrideand L-selectride favored opposite diastereomers of 7. Productdiastereomer ratios of 7 were determined by RP HPLC analysis of thecrude product. Following separation of diastereomers 7 by silica gelchromatography, (R_(C), R_(S)-7) and (S_(C), R_(S)-7) were separatelytreated with 4N HCl in 1,4-dioxane. The products (R)-8 and (S)-8 wereobtained as hydrochloride salts and the enantiopurity of the productswas determined by chiral phase HPLC. Isolated products were obtained ingreater than 95% purity as judged by ¹H NMR or HPLC-UV/MS analysis. For1-3 that have not been experimentally characterized in the scientificliterature, the (R_(C)) and (S_(C)) designations of 7 were assumed basedon their optical rotation data and HPLC chromatographic profile comparedto close structural analogs.

General Procedure “A” for Synthesis of N-tert-butanesulfinyl Amines5-10. Ti(OEt)4 (2.2 eq.) was added to a mixture of ketone (1.0 eq.) and(R)-tert-butanesulfinamide (1.2 eq.) in a glass microwave vial, sealedand the neat mixture was subjected to microwave heating at 70° C. for 1h, cooled, diluted with EtOAc and added to a saturated solution ofNaCl(aq) (0.1 mL/mmol Ti(OEt)4) with stirring. The resulting suspensionwas vacuum-filtered through Celite, concentrated and dissolved in THF(1.7 mL/mmol ketone) and CuSO4 (1.0 eq.) and NaBH4 (1.2 eq.) were addedat 21° C. After 5 h, acetic acid was added, stirred for 5 min, andconcentrated and re-suspended in CH2Cl₂, vacuum-filtered through Celiteand concentrated. Products were analyzed by HPLC to determinediastereomeric ratio, then purified by silica gel flash columnchromatography as described below. Product purity was determined by HPLCto be >95% in all examples. See Example 4, below, for examples.

General Procedure “B” for Synthesis of N-tert-butanesulfinyl Amines. Themethod is the same as A, above, but the concentrate was dissolved in THF(1.7 mL/mmol ketone) and cooled to −45° C. L-Selectride (1.2 eq., 1 Msolution in THF) was added at −45° C. After 5 h, acetic acid was added.The mixture was removed from the cold, stirred for 5 min, concentratedby rotary evaporation, re-suspended in CH2Cl2, vacuum-filtered throughCelite and the filtrate was concentrated. Products were analyzed by HPLCto determine diastereomeric ratio and purified by silica gel flashcolumn chromatography as described for individual products below.Product purity was determined by HPLC to be >95% in all examples. SeeExample 5 for purity analysis.

General Procedure for Removal of the N-tert-butanesulfinyl Group.N-tert-butanesulfinyl amines (i.e., 5-10) were dissolved in 4 N HCl in1,4-dioxane. After 5-12 hours, the mixture was diluted with diethylether (2 eq.) to effect precipitation of the product amine hydrochloridesalts. The suspension was vacuum-filtered and dried under high-vacuum toprovide amine hydrochlorides as white solids. See Example 4 forexamples.

General Procedure “C” for Amines from Oximes.

O-benzylhydroxylamine (1.42 mmol, 2.1 eq.) and pyridine (1.74 mmol, 1.4eq.) were added to a solution of 1-(aryloxy)propan-2-one (1.24 mmol, 1.0eq.) in ethanol (12 mL) at 21° C. and the flask was immersed in a 45° C.oil bath. After 2 days, the mixture was concentrated, and the reactionconcentrate was diluted with ethyl acetate and washed with water. Theorganic layer was dried (Na₂SO₄), filtered, and concentrated. Theproduct was purified by silica gel flash column chromatography on aCombiFlash (0 to 70% ethyl acetate/hexanes) to provide oxime (1.14mmol, >92% yield) as a pale yellow oil that was generally a 3.8:1.0ratio of oxime isomers by 1H NMR.

General Procedure “D” for Amine Enantiomers from Diastereomers.

See Example 4, Scheme 1 for examples.

Racemic 1. 1-(2,6-dimethylphenoxy)-N-methylpropan-2-amine

For 13: Rf=0.23 (10% methanol in dichloromethane); Commerciallyavailable.

Scheme 2:

Synthetic Procedure for synthesis of cyclic amine intermediate 2 whereF=nitrogen, A, B, D, E=carbon R, R1, R3, R4=Hydrogen andR₂=methyl(Compound 2, Scheme 1) a. DIEA, ACN reflux overnight; b.Na₂S₂O₄K₂CO₃ EtOH/H₂O 50° C. 2 h; c. LAH THF reflux overnight.

(R)-mexiletine HCl Compound (R)-2a (R)-(−)-Mexiletine Hydrochloride

Prepared from (R_(C), R_(S))-5 (60.7 mg, 0.213 mmol) using the generalprocedure provided (R)-1 hydrochloride (80% yield). (R)-1 had e.r.>99:1(R:S) using chiral HPLC method described below. (R)-1 hydrochloride: (¹HNMR, ¹³C NMR, MS) in agreement with literature values. [α]_(D) ²⁰ −2.6(c 0.62, CH₃OH); literature values [α]_(D) ²⁰ −2.9 (c 1.0, CH₃OH),[α]_(D) ²⁰ −2.4 (c 2.0, CH₃OH). ¹H NMR for (R)-(−)-Mexiletinehydrochloride (300 MHz, CDCl₃): δ 8.77 (b, 2H), 6.97 (m, 3H), 6.99-6.89(m, 3H), 4.00-3.89 (AB of ABX, J_(AB)=9.6 Hz, 2H), 3.79 (b, 1H), 2.32(s, 6H), 1.64 (d, J=6.6 Hz, 3H) ppm. ¹³C{¹H} NMR (125 MHz, CDCl₃): δ154.7, 130.9, 129.2, 124.7, 71.8, 48.5, 16.8, 15.8 ppm. LRMS (ESI-TOF)m/z calc. for C₁₁H₁₇NO [M+H⁺] 180.1; found 180.1.

(S)-mexiletine HCl Compound (S)-2b. (S)-(+)-Mexiletine Hydrochloride

Prepared from (S_(C),R_(S))-5 using the procedure that provided (S)-1hydrochloride (79% yield). (S)-1: e.r.>99 (S:R) using chiral HPLC. (S)-1hydrochloride: (¹H NMR, ¹³C NMR, MS) in agreement with literature valuesand identical to (R)-1 characterized above. [α]_(D) ²⁰ +2.1 (c 0.66,CH₃OH); literature values [α]_(D) ²⁰ +2.6 (c 1.0, CH₃OH), [α]_(D) ²⁰+2.2 (c 2.0, CH₃OH).

Compound 9

1-(2-Methylphenoxy)propan-2-amine, was made following the generalmethod, above (83% yield) as a pale yellow oil: Rf=0.2 (15%MeOH/CH₂Cl₂): ¹H NMR (300 MHz, CDCl₃) δ 7.16 (m, 2H, HAr), 6.87 (td,J=7.5, 1.1 Hz, 1H, HAr), 6.82 (m, 1H, HAr), 3.93-3.70 (AB of ABX,J_(AB)=8.8 Hz, 2H, CH₂), 3.41 (m, 1H, CH), 2.27 (s, 3H, CH₃), 1.23 (d,J=6.6 Hz, 1H, CH₃) ppm. ESI/MS for C₁₀H₁₅NO: calc. [M+H]⁺=166.1, foundm/z=166.1.

Compound (R)-10 (R)-1-cyclopropyl-2-(2,6-dimethylphenoxy)ethan-1-aminehydrochloride. [DAR-V-143] and [DAR-V-196]

Prepared from (R_(C),S_(S))-5 as above (13% yield). (R)-1 had e.r.>96(R:S) using chiral HPLC. [α]_(D) ²⁰ −19 (c 0.41, CH₃OH); LRMS (ESI-TOF)m/z calc for C₁₃H₁₉NO [M+H⁺] 206.2; found 206.0.

Compound (S)-10 (S)-1-cyclopropyl-2-(2,6-dimethylphenoxy)ethan-1-aminehydrochloride

Prepared from (Sc, Ss)-5 using the general procedure provided (S)-1hydrochloride (49% yield). (S)-1 had e.r.>96 (R:S) using chiral HPLC.[α]_(D) ²⁰ +30 (c 0.36, CH₃OH); ¹H NMR (300 MHz, CDCl₃): δ 8.91 (b, 2H),6.95 (m, 3H), 4.11 (m, 2H), 2.82 (m, 1H), 2.33 (s, 6H), 1.45 (m, 1H),0.86 (m, 1H), 0.75 (m, 2H), 0.45 (m, 1H) ppm. LRMS (ESI-TOF) m/z calcfor C₁₃H₁₉NO [M+H⁻] 206.2; found 206.0.

Compound rac 10. 1-cyclopropyl-2-(2,6-dimethylphenoxy)ethanamine, wasmade according to the general procedure above (85% yield) as a paleyellow oil/solid. Rf=0.17 (10% MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl₃) δ7.03-6.90 (m, 3H, HAr), 3.90-3.77 (AB of ABX, J_(AB)=9.0 Hz, 2H, CH₂),2.41 (m, 1H, overlapping with neighboring peak, CH), 2.32 (s, 6H,2×CH₃), 0.96 (m, 1H, CH), 0.57 (m, 2H), 0.32 (m, 2H) ppm.

Compound 11

1-(2,6-dimethylphenoxy)-N-methylpropan-2-amine, [DAR-III-149] was madeaccording to the general procedure above (38% yield) as a pale yellowoil/solid. Rf=0.23 10% MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.93(m, 3H, HAr), 6.43 (broad s, 1H), 3.93 (m, 2H, CH₂), 3.58 (m, 1H, CH),2.86 (s, 3H, NCH₃), 2.30 (s, 6H, 2×CH₃), 1.52 (d, J=6.6 Hz, 3H, CH₃)ppm.

Compound 12. 1-(2,6-dimethylphenoxy)-3,3-dimethylbutan-2-amine

ESI/MS: calculated C₁₄H₂₃NO m/z=221.2, found m/z=222.0 [M+H]. ¹H NMR(CDCl₃): 1.03 (s, 9H), 2.31 (s, 6H), 3.12-3.16 (m, 1H), 3.75-3.87 (m,2H), 6.89-6.94 (m, 1H), 6.96-7.02 (m, 2H).

Compound (R)-13 (R)-(+)-2-(2,6-dimethylphenoxy)-1-phenylethanaminehydrochloride

Prepared from (S_(C), R_(S))-8 as above (78% yield). (¹H NMR, ¹³C NMR,HRMS) in agreement with literature values. [α]_(D) ²⁰ −4.0 (c 0.63,MeOH); literature for (S)-enantiomer [α]_(D) ²⁰ +3.5 (c 0.48, MeOH). ¹HNMR for (R)-(+)-2-(2,6-dimethylphenoxy)-1-phenylethanamine hydrochloride(300 MHz, CD₃OD): δ 7.56-7.44 (m, 5H), 7.01-6.89 (m, 3H), 4.78 (X ofABX, 1H), 4.16-4.04 (AB of ABX, J_(AB)=10.4 Hz, 2H), 2.20 (s, 6H) ppm.¹³C{¹H} NMR (125 MHz, CD₃OD): δ 155.6, 135.4, 131.4, 130.6, 130.3,130.1, 128.5, 125.8, 72.9, 56.7, 16.2 ppm. HRMS (ESI-TOF) m/z calc forC₁₆H₁₉NO [M+Na⁺] 264.1364; found 264.137.

Compound 14. 2-(2,6-dimethylphenoxy)-1-(4-methoxyphenyl)ethanamine

ESI/MS: m/z=[M+H ¹H NMR (CDCl₃): 2.26 (s, 6H), 3.79-3.82 (m, 2H), 3.80(s, 3H), 4.39-4.43 (m, 1H), 6.85-6.92 (m, 3H), 6.97-6.99 (m, 2H), 7.36(s, J=8.8 Hz, 2H).

Compound 15. 2-(2,6-dimethylphenoxy)-1-(4-methoxyphenyl)ethanamine

ESI/MS: m/z=[M+H]¹H NMR (CDCl₃): 2.26 (s, 6H), 3.79-3.82 (m, 2H), 3.80(s, 3H), 4.39-4.43 (m, 1H), 6.85-6.92 (m, 3H), 6.97-6.99 (m, 2H), 7.36(s, J=8.8 Hz, 2H).

Compound 16.2-(2,6-dimethylphenoxy)-1-(4-(trifluoromethyl)phenyl)ethanamine

ESI/MS: m/z=[M+H]. ¹H NMR (CDCl₃): 2.23 (s, 6H), 3.78-3.88 (m, 2H), 4.51(dd, J=4.4 Hz and 4.4 Hz, 1H), 6.88-6.93 (m, 1H), 6.97-7.00 (m, 2H),7.56-7.72 (m, 4H).

Compound 17. 2-(2,6-dimethylphenoxy)-1-p-tolylethanamine

ESI/MS: m/z=[M+H]. ¹H NMR (CDCl₃): 2.29 (s, 6H), 2.36 (s, 3H), 3.78-3.87(m, 2H), 4.43 (dd, J=4.1 Hz and 8.0 Hz, 1H), 6.88-6.93 (m, 1H),6.98-7.01 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H).

Compound 18

¹H NMR (499 MHz, Chloroform-d) δ 4.70 (s, 2H), 5.38 (s, 2H), 6.24 (td,J=1.3, 6.7 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 7.22 (dd, J=2.1, 6.8 Hz,1H), 7.27-7.43 (m, 6H), 7.52 (t, J=7.8 Hz, 2H), 7.63 (td, J=1.3, 7.4 Hz,1H), 8.01-8.06 (m, 2H).

Compound 19

¹H NMR (499 MHz, Chloroform-d) δ 2.16 (s, 3H), 4.70 (s, 2H), 5.35 (s,2H), 6.17 (t, J=6.7 Hz, 1H), 7.09-7.15 (m, 1H), 7.26 (s, 1H), 7.27 (dd,J=1.1, 2.1 Hz, OH), 7.28-7.40 (m, 5H), 7.51 (t, J=7.8 Hz, 2H), 7.63 (dd,J=1.2, 14.9 Hz, OH), 7.63 (s, 1H), 8.01-8.07 (m, 2H).

Compound 20. 1-phenyl-2-(pyridin-2-yloxy)ethanamine

ESI/MS: m/z=[M+H]. 1H NMR (CDCl3): 4.00 (dd, J=7.1 Hz and 13.7 Hz, 1H),4.44 (dd, J=2.7 Hz and 13.7 Hz, 1H), 5.17 (dd, J=2.7 Hz and 7.7 Hz, 1H),6.12 (t, J=6.6 Hz, 1H), 6.66 (d, J=9.3 Hz, 1H), 7.05 (dd, J=1.7 Hz and6.6 Hz, 1H), 7.28-7.31 (m, 2H), 7.34-7.40 (m, 4H).

Compound 21

1H NMR (499 MHz, Chloroform-d) δ 2.19 (s, 3H), 4.02 (dd, J=7.7, 13.7 Hz,1H), 4.41 (dd, J=2.7, 13.7 Hz, 1H), 5.17 (dd, J=2.7, 7.7 Hz, 1H), 6.05(t, J=6.7 Hz, 1H), 6.94 (dd, J=1.9, 6.8 Hz, 1H), 7.21-7.29 (m, 1H),7.25-7.33 (m, 1H), 7.35 (dd, J=6.7, 8.4 Hz, 2H), 7.36-7.43 (m, 2H).

Compound 22

1H NMR (300 MHz, Chloroform-d) δ 0.79 (s, 9H), 0.97 (s, 14H), 2.30 (s,6H), 2.43 (s, 1H), 3.02 (dd, J=2.8, 9.4 Hz, 1H), 3.62 (t, J=9.1 Hz, 1H),3.83 (s, 1H), 3.84 (dd, J=2.8, 8.9 Hz, 1H), 6.86-7.06 (m, 3H).

Compound 23. 1-phenyl-2-(2-propylphenoxy)ethanamine

ESI/MS: calc. C₁₇H₂₁NO m/z=255.2, found m/z=256.0 [M+1]¹H NMR (CDCl₃):0.95 (t, J=7.4 Hz, 3H), 1.57 (sextet, J=7.4 Hz, 2H), 2.36 (bs, 2H),2.56-2.61 (m, 2H), 3.98-4.04 (m, 1H), 4.11 (dd, J=4.4 Hz and 9.1 Hz,1H), 4.44-4.48 (m, 1H), 6.77-6.80 (m, 1H), 6.84-6.90 (m, 1H), 7.08-7.14(m, 2H), 7.29-7.38 (m, 4H), 7.44-7.47 (m, 1H).

Compound 24. 1-phenyl-2-(2-ethoxyphenoxy)ethanamine

ESI/MS: calc. C₁₆H₁₉NO m/z=241.2, found m/z=242.0 [M+1]. ¹H NMR (CDCl₃):1.18 (t, J=7.4 Hz, 3H), 2.52 (bs, 2H), 2.65 (q, J=7.4 Hz, 2H), 3.99-4.05(m, 1H), 4.12 (dd, J=4.1 Hz and 9.1 Hz, 1H), 4.45-4.49 (m, 1H),6.77-6.80 (m, 1H), 6.86-6.91 (m, 1H), 7.08-7.15 (m, 2H), 7.29-7.38 (m,4H), 7.44-7.47 (m, 1H).

Compound 25. 1-phenyl-2-(o-tolyloxy)ethanamine

ESI/MS: calc. C₁₅H₁₇NO m/z=227.1, found m/z=228.0 [M+1]. ¹H NMR (CDCl₃):2.24 (s, 3H), 2.88 (bs, 2H), 3.98-4.05 (m, 1H), 4.13 (dd, J=4.1 Hz and9.1 Hz, 1H), 4.45-4.49 (m, 1H), 6.75-6.78 (m, 1H), 6.83-6.88 (m, 1H),7.08-7.13 (m, 2H), 7.29-7.37 (m, 4H), 7.44-7.47 (m, 1H).

Compound 26. 2-(2-methoxyphenoxy)-1-phenylethanamine

ESI/MS: calc. C₁₅H₁₇NO m/z=243.1, found m/z=244.0 [M+1]¹H NMR (CDCl₃):2.68 (bs, 2H), 3.79 (m, 3H), 4.05-4.11 (m, 1H), 4.15-4.20 (m, 1H),4.48-4.52 (m, 1H), 6.86-6.98 (m, 4H), 7.30-7.39 (m, 4H), 7.47-7.50 (m,1H).

Compound 27. 1-phenyl-2-(2-(trifluoromethyl)phenoxy)ethanamine

ESI/MS: calc. C₁₅H₁₄F₃NO m/z=281.1, found m/z=282.0 [M+1]¹H NMR (CDCl₃):2.38 (bs, 2H), 4.02-4.11 (m, 1H), 4.19-4.27 (m, 1H), 4.48-4.58 (m, 1H),6.91-6.94 (m, 1H), 6.98-7.03 (m, 1H), 7.29-7.42 (m, 4H), 7.44-7.49 (m,2H), 7.54-7.58 (m, 1H).

Compound 28. N-(2-(2,6-dimethylphenoxy)-1-phenylethyl)acetamide

ESI/MS: calc. C₁₈H₂₁NO₂ m/z=283.2, found m/z=284.0 [M+1]¹H NMR (CDCl₃):2.11 (s, 6H), 3.98-4.10 (m, 2H), 5.33-5.39 (m, 1H), 6.39-6.43 (m, 1H),6.87-6.98 (m, 3H) 7.29-7.43 (m, 4H).

Compound 29. N-(2-(2,6-dimethylphenoxy)-1-phenylethyl)benzamide

ESI/MS: calc. C₂₃H₂₃NO₂ m/z=345.2, found m/z=346.0 [M+1]. ¹H NMR(CDCl₃): 2.13 (s, 6H), 4.11 (dd, J=3.9 Hz and 9.4 Hz, 1H), 4.21 (dd,J=4.4 Hz and 9.4 Hz, 1H), 5.52-5.58 (m, 1H), 6.39-6.43 (m, 1H),6.88-6.98 (m, 4H), 7.15-7.18 (m, 1H), 7.30-7.41 (m, 4H), 7.44-7.53 (m,4H), 7.84-7.88 (1H).

Compound 30

2-(2,3-dimethylphenoxy)-N-butyl-1-phenylethanamine was made according tothe general method above 66% yield) as a pale yellow oil that solidifiedover time. Rf=0.25 (2% MeOH/CH2Cl2) 7.49-7.46 (m, 2H, HAr), 7.41-7.29(m, 3H, HAr), 7.02 (t, J=8.0 Hz, 1H, HAr), 6.79 (d, J=7.4 Hz, 1H, HAr),6.67 (d, J=8.0 Hz, 1H, HAr), 4.17 (app dd, J=8.2, 3.9 Hz, 1H, CH),4.10-3.99 (m, 2H, CH₂), 2.59 (t, J=6.9 Hz, 2H, CH₂), 2.30 (s, 3H, CH₃),2.19 (s, 3H, CH₃), 1.54 (m, 2H, CH₂), 1.40 (m, 2H, CH₂), 0.94 (t, J=7.4Hz, 3H, CH₃) ppm.

Compound 31

2-(2,3-dimethylphenoxy)-N-propyl-1-phenylethanamine was made by themethod above (66% yield) as a pale yellow oil that solidified over time.Rf=0.23 (2% MeOH/CH₂Cl₂); ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.46 (m, 2H,HAr), 7.42-7.29 (m, 3H, HAr), 7.03 (t, J=7.7 Hz, 1H, HAr), 6.79 (d,J=7.1 Hz, 1H, HAr), 6.68 (d, J=8.0 Hz, 1H, HAr), 4.18 (app dd, J=8.5,4.1 Hz, 1H, CH), 4.10-3.99 (m, 2H, CH₂), 2.56 (t, J=7.1 Hz, 2H, CH₂),2.30 (s, 3H, CH₃), 2.19 (s, 3H, CH₃), 1.58 (m, 2H, CH₂), 0.96 (t, J=7.7Hz, 3H, CH₃) ppm.

Compound 32

2-(2,3-dimethylphenoxy)-1-phenylethanol, Rf=0.73 (2% methanol indichloromethane); ¹H NMR (300 MHz, CDCl₃) δ 7.50-7.46 (m, 2H, HAr),7.44-7.31 (m, 3H, HAr), 7.04 (t, J=8.0 Hz, 1H, HAr), 6.82 (d, J=7.4 Hz,1H, HAr), 6.69 (d, J=8.2 Hz, 1H, HAr), 5.17 (dd, J=8.5, 3.6 Hz, 1H, CH),4.15-4.00 (AB of ABX, J_(AB)=9.6 Hz, 2H, CH₂), 2.31 (s, 3H, CH₃), 2.21(s, 3H, CH₃) ppm.

Compound 33

2-(2,3-dimethylphenoxy)-N-ethyl-1-phenylethanamine, was made accordingto the general procedure above (97% yield) as a pale yellow oil thatsolidified over time. Rf=0.18 (4% MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl₃)δ 7.49-7.46 (m, 2H, HAr), 7.41-7.29 (m, 3H, HAr), 7.01 (t, J=8.0 Hz, 1H,HAr), 6.78 (d, J=7.4 Hz, 1H, HAr), 6.68 (d, J=8.3 Hz, 1H, HAr), 4.20(app dd, J=8.0, 4.7 Hz, 1H, CH), 4.12-4.03 (m, 2H, CH₂), 2.64 (q, J=7.2Hz, 2H, CH₂), 2.29 (s, 3H, CH₃), 2.17 (s, 3H, CH₃), 1.17 (t, J=7.1 Hz,3H, CH₃) ppm.

Compound 34

2-(2,3-dimethylphenoxy)-N-methyl-1-phenylethanamine, was prepared by thegeneral method above (97% yield) as a pale yellow oil that solidifiedover time. Rf=0.33 (5% MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl3) δ 7.48-7.46(m, 2H, HAr), 7.42-7.3 (m, 3H, HAr), 7.01 (t, J=7.7 Hz, 1H, HAr), 6.78(d, J=7.4 Hz, 1H, HAr), 6.68 (d, J=8.3 Hz, 1H, HAr), 4.02 (m, 3H, CH,CH₂), 2.42 (s, 3H, NCH₃), 2.29 (s, 3H, CH₃), 2.18 (s, 3H, CH₃) ppm.

Compound 35

2-(2,3-dimethylphenoxy)-1-phenylethanamine, was made according to theabove procedure (58% yield) as a pale yellow oil that solidified overtime. Rf=0.27 (5% MeOH/CH2Cl2); ¹H NMR (300 MHz, CDCl₃) δ 7.5-7.47 (m,2H, HAr), 7.42-7.28 (m, 3H, HAr), 7.03 (t, J=7.7 Hz, 1H, HAr), 6.79 (d,J=7.5 Hz, 1H, HAr), 6.68 (d, J=8.0 Hz, 1H, HAr), 4.47 (dd, J=7.7, 3.8Hz, 1H, CH), 4.13-3.95 (AB of ABX, J_(AB)=9.1 Hz, 2H, CH₂), 2.39 (broads, 2H, NH₂), 2.30 (s, 3H, CH₃), 2.19 (s, 3H, CH₃) ppm.

Compound 36. 2-(2,3-dimethylphenoxy)-N-methoxy-ethyl-1-phenylethanamine

¹H NMR (300 MHz, Chloroform-d) δ 1.27 (d, J=6.5 Hz, 7H), 2.29 (s, 6H),3.58-3.79 (m, 2H), 4.14-4.31 (m, 1H), 6.92 (dd, J=6.2, 8.4 Hz, 1H),6.96-7.05 (m, 2H), 7.25 (s, 1H).

Compound 37

¹H NMR (300 MHz, Chloroform-d) δ 0.98 (t, J=7.4 Hz, 3H), 1.19 (d, J=6.4Hz, 3H), 1.52-1.69 (m, 4H), 2.29 (s, 6H), 2.48 (s, 1H), 2.70 (dddd,J=6.8, 8.0, 11.1, 38.0 Hz, 2H), 3.07-3.21 (m, 1H), 3.62-3.77 (m, 2H),6.85-7.05 (m, 3H).

Compound 38

1-(2,6-dimethylphenoxy)-N-propylpropan-2-amine, was made following thegeneral method above (38% yield) as a pale yellow oil that solidifiedover time. Rf=0.24 (10% MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl₃) δ7.03-6.90 (m, 3H, HAr), 3.70 (m, 2H, CH₂), 3.17 (m, 1H, CH), 2.82-2.62(m, 2H, CH₂), 2.50 (broad s, 1H), 2.31 (s, 6H, 2×CH₃), 1.62 (m, 2H,CH₂), 1.28 (d, J=6.6 Hz, 3H, CH₃), 0.99 (t, J=7.4 Hz, 3H, CH₃) ppm.

Compound 39

1-(2,6-dimethylphenoxy)-N-butylpropan-2-amine, was made according to thegeneral procedure above (60% yield) as a pale yellow oil that solidifiedover time. Rf=0.31 (10% MeOH/CH₂Cl₂): ¹H NMR (300 MHz, CDCl₃) δ7.02-6.91 (m, 3H, HAr), 4.21 (broad s, 1H, NH), 3.83-3.73 (AB of ABX,J_(AB)=9.6 Hz, 2H, CH₂), 3.27 (m, 1H, CH), 2.95-2.76 (m, 2H, CH₂), 2.30(s, 6H, 2×CH₃), 1.65 (m, 2H, CH₂), 1.43 (m, 2H, CH₂), 1.28 (d, J=6.6 Hz,3H, CH₃), 0.98 (t, J=7.2 Hz, 3H, CH₃) ppm.

Compound 40. 1-(2,6-dimethylphenoxy)-N-methoxy-ethyl-2-amine

Rf=0.36 (10% MeOH in DCM); ¹H NMR (300 MHz, CDCl₃) δ 7.02-6.89 (m, 3H,HAr), 3.76-3.67 (m, 2H, CH₂), 3.59 (app t, J=4.9 Hz, 2H), 3.40 (s, 3H,OCH₃), 3.22-3.12 (m, 2H, CH₂), 3.01-2.85 (m, 2H, CH₂), 2.54 (broad s,1H, NH), 2.31 (s, 6H, 2×CH₃), 1.22 (d, J=6.6 Hz, 3H, CH₃) ppm.

Compound 41

1-(2,6-dimethylphenoxy)-N-ethylpropan-2-amine, was made following thegeneral method above (40% yield) as a pale yellow oil that solidifiedover time. Rf=0.19 (10% MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl₃) δ7.02-6.92 (m, 3H, HAr), 6.23 (broad s, 1H), 4.03-3.96 (AB of ABX,J_(AB)=10.1 Hz, 2H, CH₂), 3.61 (m, 1H, CH), 3.24 (m, 2H, CH₂), 2.30 (s,6H, 2×CH₃), 1.51 (d, J=6.9 Hz, 3H, CH₃), 1.45 (t, J=6.4 Hz, 3H, CH₃)ppm.

Compound 42

1-(2,6-dimethylphenoxy)-N-benzylpropan-2-amine, was made according tothe above general procedure (80% yield) as a beige solid. Rf=0.24 (5%MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl3) δ 7.40-7.3 (m, 4H, HAr), 7.27 (m,1H, HAr, overlapping with solvent signal), 7.01 (m, 2H, HAr), 6.93 (m,1H, HAr), 4.00-3.87 (AB quartet, J=13.1 Hz, 2H, CH₂), 3.77-3.69 (m, 2H,CH₂), 3.20 (m, 1H, CH), 2.29 (s, 6H, 2×CH₃), 1.22 (d, J=6.0 Hz, 3H, CH₃)ppm.

Compound 43

1-(2,6-dimethylphenoxy)-N-phenylpropan-2-amine, was made according tothe general method above (61% yield) as a pale yellow oil. Rf=0.34 (20%EtOAc/hexanes): ¹H NMR (300 MHz, CDCl₃) δ 7.20 (t, J=7.7 Hz, 2H, HAr),7.00 (m, 2H, HAr), 6.92 (m, 1H, HAr), 6.75-6.69 (m, 3H, HAr), 4.13(broad s, 1H), 3.89 (m, 1H, CH), 3.85-3.80 (m, 2H, CH₂), 2.27 (s, 6H,2×CH₃), 1.47 (d, J=6.6 Hz, 3H, CH₃) ppm.

Compound 44

1-(2,6-dimethylphenoxy)-N-(2-phenylethyl)propan-2-amine, was madeaccording to the above procedure (66% yield) as a beige solid. Rf=0.25(5% MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl₃) δ 7.31 (m, 2H, HAr), 7.26 (m,2H, HAr, overlapping with solvent signal), 7.22 (t, J=7.1 Hz, 1H, HAr),7.01 (m, 2H, HAr), 6.92 (m, 1H, HAr), 3.67 (m, 2H, CH₂), 3.15 (m, 1H,CH), 3.06 (m, 1H, CH), 2.96-2.83 (m, 2H, CH₂), 2.25 (s, 6H, 2×CH₃), 1.18(d, J=6.1 Hz, 3H, CH₃) ppm.

Compound 45

¹H NMR (499 MHz, Chloroform-d) δ 1.15-1.33 (m, 5H), 1.72 (dd, J=5.6, 9.7Hz, 4H), 1.82-1.90 (m, 1H), 1.93 (d, J=4.6 Hz, 1H), 3.22 (tt, J=4.1, 9.5Hz, 1H), 4.00 (s, 1.6H), 4.35 (s, 0.4H), 5.05 (s, 0.4H), 5.11 (s, 1.6H),7.25-7.39 (m, 5H).

Compound 46

Rf=0.56 (5% ethyl acetate/hexanes); ¹H NMR (300 MHz, CDCl₃, 2 isomers) δ7.41-7.28 (m, 10H, HAr), 7.03-6.90 (m, 6H, HAr), 5.16 (s, 2H, CH₂), 5.03(s, 2H, CH₂), 4.65 (s, 2H, CH₂), 4.15 (s, 2H, CH₂), 2.41 (m, 1H, CH),2.31 (s, 6H, 2×CH₃), 2.27 (s, 6H, 2×CH₃), 2.05 (m, 1H, CH), 1.18 (m,2H), 1.03-0.94 (m, 4H), 0.92-0.85 (m, 2H) ppm.

Compound 47

1-(pyridin-2-yloxy)propan-2-one O-benzyl oxime, Rf=0.28 (75% ethylacetate/hexanes); ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.30 (m, 5H, HAr), 7.19(m, 1H, HAr), 6.60 (m, 1H, HAr), 6.16 (td, J=6.8, 1.3 Hz, 1H, HAr), 5.12(s, 2H, CH₂), 4.70 (s, 2H, CH₂), 1.89 (s, 3H, CH₃) ppm.

General Procedure for Synthesis of (Pyridin-2-yloxy)propan-2-amine,Compound 48

A 1M solution of borane-tetrahydrofuran complex in THF (5.0 eq.) wasadded to a stirred solution of 1-(pyridin-2-yloxy)propan-2-one O-benzyloxime (1.0 eq.) in THF (3.8 mL) at 21° C. After 14 hours, the reactionwas stopped by dropwise addition of 1 M HCl_((aq)) (pH 3) and then 10%(wt/wt) Na₂CO_(3(aq)) was added (pH 9), Celite (3 mL) was added,concentrated and dry-loaded onto a silica gel column and flashed usinggradient elution (10% methanol in CH2Cl2 initial, then 1%NH₄OH_((aq))/20% MeOH/79% CH2Cl2). The isolated product was dissolved in20% MeOH/CH2Cl2, filtered through a Whatman #1 filter paper andconcentrated to give 23 (50% yield) as a pale yellow solid. For 23:Rf=0.46 (1% NH₄OH_((aq))/20% MeOH/79% CH2Cl2): ¹H NMR (300 MHz, CD₃OD) δ7.69 (dd, J=6.6, 1.9 Hz, 1H, HAr), 7.57 (overlapping ddd, J=9.0, 6.8,2.2 Hz, 1H, HAr), 6.58 (d, J=7.8 Hz, 1H, HAr), 6.44 (td, J=6.6, 1.1 Hz,1H, HAr), 4.32-4.16 (AB of ABX, J_(AB)=14.0 Hz, 2H, CH₂), 3.76 (m, 1H,CH), 1.36 (d, J=6.9 Hz, 1H, CH₃) ppm. ESI/MS for C₈H₁₂N₂O: calc.[M+H]⁺=153.1, found m/z=153.1.

Compound 49

1-(2-Propylphenoxy)propan-2-amine was made following the above procedure(94% yield) as a pale yellow oil. Rf=0.24 (15% MeOH/CH2Cl2): ¹H NMR (300MHz, CDCl₃) δ 7.15 (m, 2H, HAr), 6.89 (td, J=7.4, 1.4 Hz, 1H, HAr), 6.82(m, 1H, HAr), 3.92-3.70 (AB of ABX, J_(AB)=8.8 Hz, 2H, CH₂), 3.41 (m,1H, CH), 2.64 (t, J=7.5 Hz, 2H, CH₂), 1.64 (m, 2H, CH₃), 1.23 (d, J=6.6Hz, 1H, CH₃), 0.98 (t, J=7.1 Hz, 3H, CH₃) ppm. ESI/MS for C₁₂H₁₉NO:calculated [M+H]⁺=194.1, found m/z=194.1.

Compound 50

1-(2-Ethylphenoxy)propan-2-amine was made according to the procedureabove (76% yield) as a pale yellow oil. Rf=0.22 (15% MeOH/CH2Cl2): ¹HNMR (300 MHz, CDCl₃) δ 7.16 (m, 2H, HAr), 6.92 (td, J=7.4, 1.1 Hz, 1H,HAr), 6.82 (dd, J=8.8, 0.9 Hz, 1H, HAr), 3.92-3.71 (AB of ABX,J_(AB)=9.0 Hz, 2H, CH₂), 3.41 (m, 1H, CH), 2.69 (q, J=7.5 Hz, 2H, CH₂),1.24 (t, J=7.5 Hz, 3H, CH₃), 1.23 (d, J=6.6 Hz, 1H, CH₃) ppm. ESI/MS forC₁₁H₁₇NO: calculated [M+H]⁺=180.1, found m/z=180.1.

Compound 51

1-(2-(Trifluoromethyl)phenoxy)propan-2-amine was made by the generalprocedure (71% yield) as a pale yellow oil. Rf=0.16 (15% MeOH/CH2Cl2):¹H NMR (300 MHz, CDCl₃) δ 7.57 (dd, J=7.7, 1.3 Hz, 1H, HAr), 7.48 (m,1H, HAr), 7.00 (m, 2H, HAr), 4.03-3.76 (AB of ABX, J_(AB)=8.5 Hz, 2H,CH₂), 3.44 (m, 1H, CH), 1.23 (d, J=6.6 Hz, 1H, CH₃) ppm. ESI/MS forC₁₀H₁₂F₃NO: calc. [M+H]⁺=220.1, found m/z=220.0.

Compound 52

1-(2-Methoxyphenoxy)propan-2-amine was made following the generalprocedure above (74% yield) as a pale yellow oil. Rf=0.29 (15%MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl₃) δ 6.96-6.88 (m, 4H, HAr),3.98-3.70 (AB of ABX, J_(AB)=9.4 Hz, 2H, CH₂), 3.88 (s, 3H, OCH₃), 3.41(m, 1H, CH), 1.20 (d, J=6.6 Hz, 1H, CH₃) ppm. ESI/MS for C₁₀H₁₅NO₂:calculated [M+H]⁺=182.1, found m/z=182.0.

Compound 53

¹H NMR (300 MHz, Chloroform-d) δ 1.41 (d, J=6.8 Hz, 2H), 2.04 (s, 3H),2.26 (s, 6H), 3.66-3.86 (m, 2H), 4.28-4.44 (m, 1H), 5.93 (s, 1H),6.86-7.08 (m, 3H).

Compound 54

¹H NMR (300 MHz, Chloroform-d) δ 1.54 (d, J=6.8 Hz, 3H), 2.28 (s, 6H),3.78-4.00 (m, 2H), 3.90 (s, 2H), 3.95 (dd, J=3.8, 9.1 Hz, 1H), 4.57 (m,1H), 6.64 (d, J=8.4 Hz, 1H), 6.87-7.05 (m, 3H), 7.38-7.57 (m, 3H),7.73-7.92 (m, 2H).

Compound 55

ESI/MS calculated for C₁₁H₁₇NO m/z: 179.1, found m/z=180.0 [M+H]⁺.

Compound 56

¹H NMR (300 MHz, Methanol-d₄) δ 1.45 (dd, J=1.5, 6.7 Hz, 3H), 2.35 (s,3H), 3.85-4.20 (m, 2H), 7.04 (t, J=7.7 Hz, 1H), 7.17 (d, J=6.7 Hz, 1H),7.25 (d, J=7.4 Hz, 1H).

Compound 57. (S)-1-(2-chloro-6-methylphenoxy)propan-2-aminehydrochloride

ESI/MS: calculated C₁₀H₁₄ClNO m/z=199.1, found m/z=200.0 [M+1] ¹H NMR(MeOH-d6): 1.32 (d, J=6.2 Hz, 3H), 2.32 (s, 3H), 3.82-3.96 (m, 3H), 4.18(bs, 1H), 6.94 (t, J=7.8 Hz, 1H), 7.04-7.08 (m, 1H), 7.17-7.21 (m, 1H).

Compound 58

¹H NMR (300 MHz, Methanol-d₄) δ 1.45 (d, J=6.7 Hz, 2H), 3.70-3.81 (m,1H), 4.06 (dd, J=6.7, 10.2 Hz, 1H), 4.24 (dd, J=3.8, 10.2 Hz, 1H), 7.01(td, J=1.4, 7.6 Hz, 1H), 7.13 (dd, J=1.5, 8.3 Hz, 1H), 7.23-7.35 (m,1H), 7.40 (dd, J=1.6, 7.9 Hz, 1H).

Compound 59

¹H NMR (300 MHz, Chloroform-d) δ 2.29 (t, J=0.6 Hz, 6H), 4.30 (s, 2H),6.92-7.08 (m, 3H).

Compound 60

ESI/MS calculated for C₁₃H₁₉NO m/z: 205.2, found m/z=206.0 [M+H]⁺.

Compound 61

ESI/MS calculated for C₁₃H₁₉NO m/z: 205.2, found m/z=206.0 [M+H]⁺.

Compound 62

ESI/MS calculated for C₁₃H₁₉NO m/z: 205.2, found m/z=206.0 [M+H]⁺.

Compound (R-) 63a.(R)-1-cyclopropyl-2-(3,5-dimethylphenoxy)ethan-1-amine hydrochloride

Prepared from (R_(C),S_(S))-5 using the general procedure provided (R)-1hydrochloride (47% yield). LRMS (ESI-TOF) m/z calc for C₁₃H₁₉NO [M+H⁺]206.2; found 206.0.

Compound (S)-63b. (S)-1-cyclopropyl-2-(2,6-dimethylphenoxy)ethan-1-aminehydrochloride

Prepared from (S_(C),S_(S))-) using the above method, (49% yield).[α]_(D) ²⁰ +30 (c 0.36, CH₃OH); ¹H NMR (300 MHz, CDCl₃): δ 8.67 (b, 2H),6.68 (s, 2H), 6.58 (s, 1H), 4.26 (m, 1H), 4.13 (m, 1H), 2.26 (s, 6H),1.15 (m, 1H), 0.53 (m, 3H), 0.16 (m, 1H) ppm. LRMS (ESI-TOF) m/z calcfor C₁₃H₁₉NO [M+H⁺] 206.2; found 206.0.

Compound 64

¹H NMR (300 MHz, Methanol-d₄) δ 1.44 (d, J=6.7 Hz, 3H), 2.24 (broad s,6H), 3.73 (pd, J=3.7, 6.7 Hz, 1H), 3.96 (dd, J=6.8, 10.3 Hz, 1H), 4.13(dd, J=3.8, 10.3 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.89-7.00 (m, 2H).

Compound 65

¹H NMR (300 MHz, Methanol-d4) δ 0.45-0.63 (m, 2H), 0.78 (ddd, J=2.0,3.8, 8.0 Hz, 2H), 1.11 (m, 1H), 2.24 (broad s, 6H), 2.84 (ddd, J=3.4,6.3, 10.0 Hz, 1H), 4.06-4.28 (m, 2H), 6.77-6.86 (m, 1H), 6.90-7.00 (m,2H).

Compound 66

¹H NMR (300 MHz, Methanol-d₄) δ 2.23 (d, J=2.1 Hz, 6H), 4.22-4.36 (m,2H), 4.79 (dd, J=4.9, 7.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 6.94 (m, 2H),7.42-7.60 (m, 5H).

Compound 67

1-(2,6-dimethylphenoxy)-N-butylpropan-2-amine was made according to thegeneral method above(52% yield) as a pale yellow oil that solidifiedover time. Rf=0.36 (10% MeOH/CH2Cl2): ¹H NMR (300 MHz, CDCl₃) δ7.02-6.89 (m, 3H, HAr), 3.76-3.67 (m, 2H, CH₂), 3.59 (app t, J=4.9 Hz,2H), 3.40 (s, 3H, OCH₃), 3.22-3.12 (m, 2H, CH₂), 3.01-2.85 (m, 2H, CH₂),2.54 (broad s, 1H, NH), 2.31 (s, 6H, 2×CH₃), 1.22 (d, J=6.6 Hz, 3H, CH₃)ppm.

Compound 68

¹H NMR (300 MHz, Methanol-d₄) δ 0.14-0.82 (m, 9H), 0.91-1.09 (m, 1H),2.25 (s, 6H), 2.75-2.91 (m, 1H), 2.99-315 (m, 1H), 3.16-3.32 (m, 1H),3.36 (dd, J=1.2, 4.5 Hz, 1H), 3.54 (td, J=2.2, 4.9 Hz, 1H), 3.80-4.14(m, 2H), 6.54 (s, 2H), 6.56 (d, J=4.9 Hz, 1H).

Compound 69

¹H NMR (300 MHz, MeOH-d4) δ 2.24 (d, J=0.7 Hz, 6H), 2.53-2.76 (m, 1H),3.35 (s, 1H), 3.33-3.56 (m, 2H), 3.96-4.13 (m, 2H), 6.49-6.61 (m, 3H),7.22-7.47 (m, 5H).

Compound 70. (rac)-(+)-2-(3,5-dimethylphenoxy)-1-phenylethanaminehydrochloride

Prepared from (rac)-8 by the general procedure provided the titleproduct (83% yield): ¹H NMR (300 MHz, CD₃OD): δ 7.56-7.46 (m, 5H), 6.64(s, 3H), 4.74 (dd, J=8.3, 4.4 Hz, 1H), 4.35-4.24 (AB of ABX, J_(AB)=10.5Hz, 2H), 2.27 (s, 6H) ppm. LRMS (ESI-TOF) m/z calc for C₁₆H₁₉NO [M+H⁺]242.2; found 242.0.

Compound (R-)-71. (R)-1-phenoxypropan-2-amine hydrochloride

Prepared from (R_(C), S_(S))-5 above using the general procedureprovided (R)-1 hydrochloride (65% yield): ¹H NMR (300 MHz, CD₃OD): δ7.30 (m, 2H), 7.01-6.96 (m, 3H), 4.22-3.97 (AB of ABX, J_(AB)=10.5 Hz,2H), 3.73 (m, 1H), 1.44 (d, J=6.9 Hz, 3H) ppm. LRMS (ESI-TOF) m/z calc.for C₉H₁₃NO [M+H⁺] 152.1; found 152.2.

Compound 72

¹H NMR (300 MHz, MeOH-d4) δ 1.44 (d, J=6.7 Hz, 1H), 3.71 (ddd, J=3.7,7.1, 10.5 Hz, OH), 4.00 (dd, J=7.1, 10.3 Hz, OH), 4.20 (dd, J=3.6, 10.2Hz, 1H), 7.00 (m, 3H), 7.30 (m, 2H).

Compound 73

¹H NMR (300 MHz, Methanol-d₄) δ 1.15-1.39 (m, 5H), 1.63-2.05 (m, 6H),2.30 (s, 6H), 3.41 (td, J=3.7, 7.2 Hz, 1H), 3.66 (s, 1H), 3.86-4.05 (m,1H), 6.87-7.07 (m, 2H).

Compound 74

¹H NMR (300 MHz, CHCl₃-d) δ 0.14-0.45 (m, 2H), 0.45-0.92 (m, 3H), 2.27(s, 3H), 2.34 (dt, J=9.0, 2.7 Hz, 1H), 3.35-3.77 (m, 1H), 3.80-4.20 (m,2H), 4.46 (dd, J=2.6, 12.1 Hz, 1H), 6.89 (t, J=7.4 Hz, 1H), 6.98 (dt,J=7.6, 1.9 Hz, 1H), 7.06 (dt, J=7.4, 1.2 Hz, 1H)

Compound 75

¹H NMR (300 MHz, Methanol-d₄) δ 2.19 (s, 3H), 2.24 (s, 3H), 4.18-4.37(m, 2H), 4.73 (dd, J=4.2, 8.4 Hz, 1H), 6.73 (dd, J=2.8, 8.2 Hz, 1H),6.82 (d, J=2.7 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 7.42-7.58 (m, 5H).

Compound 76

¹H NMR (300 MHz, Methanol-d4) δ 1.15-1.38 (m, 6H), 1.75 (d, J=10.8 Hz,1H), 1.88 (d, J=9.7 Hz, 6H), 2.36 (s, 3H), 3.43 (td, J=3.5, 7.0 Hz, 1H),4.01-4.22 (m, 2H), 7.04 (t, J=7.8 Hz, 1H), 7.12-7.31 (m, 2H).

Compound 77

¹H NMR (300 MHz, Methanol-d4) δ 0.54 (qd, J=4.9, 10.2 Hz, 2H), 0.70-0.82(m, 2H), 1.07-1.24 (m, 1H), 2.20 (s, 3H), 2.2.4 (s, 3H), 2.79 (ddd,J=3.5, 7.0, 10.4 Hz, 1H), 4.09 (dd, J=7.0, 10.3 Hz, 1H), 4.23 (dd,J=3.5, 10.3 Hz, 1H), 6.72 (dd, J=2.7, 8.2 Hz, 1H), 6.80 (d, J=2.8 Hz,1H), 7.03 (d, J=8.2 Hz, 1H).

Compound 78. 2-(3,5-bis(trifluoromethyl)phenoxy)-1-phenylethan-1-amine

ESI/MS: calc. C₁₆H₁₃F₆NO m/z=349.1, found m/z=350.0 [M+1] ¹H NMR (300MHz, CHCl₃-d) δ 4.02 (t, J=8.7 Hz, 1H), 4.15 (dd, J=3.8, 8.7 Hz, 1H),4.48 (dd, J=3.8, 8.6 Hz, 1H), 7.27-7.49 (m, 8H).

Compound 79

LRMS (ESI-TOF) m/z Expected [M+H]⁺=243, Obs. [M+H]⁺=243

Compound 80

¹H NMR (300 MHz, Chloroform-d) δ 2.62-2.85 (m, 3H), 3.38 (s, 3H), 3.50(m, 3H), 4.08-4.21 (m, 3H), 7.27 (d, J=10.2 Hz, 2H), 7.32-7.50 (m, 6H).

Compound 81. 1-phenyl-2-(3-(trifluoromethyl)phenoxy)ethan-1-amine

ESI/MS: calculated C₁₅H₁₄F₃NO m/z=281.1, found m/z=282.0 [M+1].

Compound 82. 1-phenyl-2-(2-(trifluoromethyl)phenoxy)ethan-1-amine

ESI/MS: calculated C₁₅H₁₄F₃NO m/z=281.1, found m/z=282.0 [M+1].

Compound 83. 2-methyl-N-(1-phenyl-2-(m-tolyloxy)ethyl)propane-2

ESI/MS: calculated C₁₅H₁₇NO m/z=227.1, found m/z=228.0 [M+1].

Compound 84

MS: [M+H]⁺=288. Expected [M+H]⁺=288

Compound 85

MS: [M+H]⁺=220. Expected [M+H]⁺=220

Compound 86

MS: [M+H]⁺=166. Expected [M+H]⁺=166

Compound 87

¹H NMR (300 MHz, Chloroform-d) δ 0.63-1.41 (m, 5H), 1.09 (d, J=5.1 Hz,3H), 1.43-2.0 (m, 5H), 3.07-3.31 (m, 2H), 3.37-3.50 (m, 1H)

Compound 88

A mixture of rotamers. ¹H NMR (300 MHz, Methanol-d₄) δ 2.14-2.40 (m,3H), 4.17-4.26 (m, 2H), 4.32-4.49 (m, 1H), 7. 50-7.72 (m, 6H), 7.83-8.29(m, 2H).

Compound 89

¹H NMR (300 MHz, Methanol-d4) δ 1.07-1.54 (m, 5H), 1.64-1.98 (m, 6H),2.28 (s, 6H), 3.32 (s, 3H), 4.04-4.23 (m, 2H), 6.58-6.67 (m, 3H).

Compound 90

¹H NMR (300 MHz, Chloroform-d) δ 2.24 (s, 3H), 2.68-2.86 (m, 2H), 3.37(s, 3H), 3.53 (td, J=1.4, 4.5, 5.0 Hz, 2H), 4.02-4.19 (m, 2H), 4.21 (dd,J=4.1, 8.3 Hz, 1H), 6.71-6.95 (m, 2H), 7.04-7.20 (m, 2H), 7.21-7.44 (m,3H), 7.44-7.53 (m, 2H).

Compound 91

¹H NMR (300 MHz, Chloroform-d) δ 6.68 (s, 2H), 6.58 (s, 1H), 4.04-4.37(m, 3H), 2.26 (s, 6H), 0.52 (br. s., 4H), 0.16 (br. s., 1H)

Compound 92

¹H NMR (300 MHz, ChCl₃-d) δ 2.28 (s, 6H), 2.61-2.87 (m, 2H), 3.52-3.74(m, 2H), 3.94-4.10 (m, 2H), 4.10-4.19 (m, 1H), 6.50-6.64 (m, 2H),7.22-7.46 (m, 6H).

Compound 93

ESI/MS: MW calculated for C₁₈H₁₇F₆NO₂: 393.1 Observed: 394.0 [M+H]⁺

2-(3-methylpyridin-2-yloxy)-1-phenylethanamine, KJO-VIII-068

¹H NMR (CDCl₃): 2.19 (s, 3H), 2.74 (bs, 2H), 4.02 (dd, J=7.7 Hz and 13.7Hz, 1H), 4.41 (dd, J=2.7 Hz and 13.7 Hz, 1H), 5.17 (dd, J=2.2 Hz and 7.7Hz, 1H), 6.05 (t, J=6.6 Hz, 1H), 6.94 (d, J=6.6 Hz, 1H), 7.23 (d, J=6.6Hz, 1H), 7.29 (t, J=7.1 Hz, 1H), 7.35 (t, J=7.7 Hz, 2H), 7.40 (d, J=7.1Hz, 2H).

Compound 94. 2-((3-methylpyridin-2-yl)oxy)-1-phenylethan-1-amine

ESI/MS: calculated C₁₄H₁₄N₂O₂ m/z=228.1, found m/z=229.0 [M+1] ¹H NMR(300 MHz, Chloroform-d) δ 2.10 (s, 3H), 4.19 (d, J=6.6 Hz, 2H), 4.65 (t,J=6.5 Hz, 1H), 5.95 (t, J=6.8 Hz, 1H), 6.92 (d, J=6.8 Hz, 1H), 7.16 (d,J=6.9 Hz, 1H), 7.24-7.38 (m, 3H), 7.39-7.50 (m, 2H).

Compound 95. 2-((4-methylpyridin-2-yl)oxy)-1-phenylethan-1-amine

ESI/MS: calculated C₁₄H₁₆N₂O m/z=228.1, found m/z=229.0 [M+1].

Compound 96.1-phenyl-2-((3-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-amine

ESI/MS: calculated C₁₄H₁₃F₃N₂O m/z=282.1, found m/z=283.0 [M+1].

Compound 97.1-phenyl-2-((4-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-amine

ESI/MS: calculated C₁₄H₁₃F₃N₂O m/z=282.1, found m/z=283.0 [M+1].

Compound 98

¹H NMR (300 MHz, Methanol-d₄) δ 2.11 (s, 6H), 2.58 (m, 8H), 3.40-3.63(m, 6H), 3.78 (s, 1H), 6.46-6.56 (m, 3H), 7.27-7.41 (m 3H), 7.46-7.57(m, 2H).

Compound 99

¹H NMR (300 MHz, Methanol-d₄) δ 3.49 (d, J=6.2 Hz, 1H), 3.71 (s, 10H),3.95 (m, 8H), 4.61-4.84 (m, 6H), 7.50-7.54 (m, 4H), 7.65-7.73 (m, 4H).

Compound 100

1-(-3-Methyl-pyridin-2-yloxy)propan-2-amine was made (31% yield) as apale yellow solid: Rf=0.44 (1% NH₄H_((aq))/20% MeOH/79% CH2Cl2): ¹H NMR(300 MHz, CD₃OD) δ 7.45 (m, 1H, HAr), 7.39 (m, 1H, HAr), 6.30 (t, J=6.9Hz, 1H, HAr), 4.06-3.89 (AB of ABX, J_(AB)=12.8 Hz, 2H, CH₂), 3.42 (m,1H, CH), 1.17 (d, J=6.6 Hz, 1H, CH₃) ppm. ESI/MS for C₉H₁₄N₂O: calc.[M+H]⁺=167.1, found m/z=167.1.

Compound 105

¹H NMR (300 MHz, Chloroform-d) δ 2.62-2.83 (m, 2H), 3.37 (s, 3H),3.44-3.56 (m, 2H), 4.07 (t, J=8.6 Hz, 1H), 4.11-4.26 (m, 2H), 6.90 (d,J=8.3 Hz, 1H), 6.94-7.05 (m, 1H), 7.25-7.46 (m, 3H), 7.45 (tt, J=1.4,7.4 Hz, 3H), 7.51-7.61 (m, 1H).

Compound 110

¹H NMR (499 MHz, CD₃OD) δ 8.32-8.41 (m, 1H), 8.25-8.32 (m, 1H),7.44-7.69 (m, 4H), 7.38 (t, J=7.68 Hz, 2H), 7.28-7.35 (m, 1H), 5.12 (dd,J=3.84, 7.68 Hz, 1H), 4.72-4.79 (m, 2H), 4.29-4.47 (m, 2H), 3.57-3.78(m, 2H), 3.39 (s, 3H). Calculated m/z for C₁₆H₂₀N₂O₂: 272.15, Observed:273.2 [M+H]⁺, 295.3 [M+Na]⁺

Compound 111

R_(f)=0.44 (1:20 MeOH/DCM), purity 98%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.18 (d, J=4.8 Hz, 1H), 7.55-7.18 (m, 7H), 4.57-4.40 (m, 2H), 2.43 (s,3H). Calculated m/z for C₁₄H₁₆N₂O m/z: 228.1, found m/z=229.00 [M+H]⁺.

Compound 112

Rf=0.45 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.47-8.26 (m, 2H), 7.85-7.30 (m, 6H), 5.11 (s, 1H), 4.35 (d, J=5.2 Hz,2H), 2.45 (s, 3H). Calculated m/z for C₁₄H₁₆N₂O m/z: 228.1, foundm/z=229.00 [M+H]⁺.

Compound 113

R_(f)=0.43 (1:20 MeOH/DCM), purity 95%+. ¹H NMR (300 MHz, DMSO-d₆) δ8.98 (s, 3H), 8.10 (d, J=10.1 Hz, 2H), 7.82-7.57 (m, 2H), 7.50-7.39 (m,4H), 4.77 (s, 1H), 4.52-4.39 (m, 2H), 2.35 (s, 3H). Calculated m/z forC₁₄H₁₆N₂O m/z: 228.1, found m/z=229.00 [M+H]⁺.

Compound 114

R_(f)=0.43 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, DMSO-d₆) δ8.90 (s, 3H), 8.50 (s, 1H), 7.87 (d, J=8.9 Hz, 1H), 7.66 (m, 3H), 7.45(m, J=6.9 Hz, 3H), 4.81 (s, 1H), 4.52 (m, J=5.3 Hz, 2H), 2.48 (s, 3H).Calculated m/z for C₁₄H₁₆N₂O m/z: 228.1, found m/z=229.00 [M+H]⁺.

Compound 115

R_(f)=0.45 (1:20 MeOH/DCM), purity 95%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.37 (s, 1H), 7.91-7.21 (m, 7H), 4.52-4.37 (m, 2H). Calculated m/z forC₁₄H₁₃F₃N₂O m/z: 282.1, found m/z=283.00 [M+H]⁺.

Compound 116

R_(f)=0.46 (1:20 MeOH/DCM), purity 95%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.12-7.02 (m, 8H), 4.70-4.59 (m, 1H), 4.45-4.31 (m, 2H). Calculated m/zfor C₁₄H₁₃F₃N₂a m/z: 282.1, found m/z=283.0 [M+H]⁺.

Compound 117

R_(f)=0.46 (1:20 MeOH/DCM), purity 95%+. Entry #10, (Notebook:MEJ-I-077) ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (s, 3H), 8.31 (s, 1H), 7.92(d, J=8.6 Hz, 1H), 7.70-7.54 (m, 3H), 7.45 (m, 3H), 4.80 (s, 1H), 4.51(m, J=5.1 Hz, 2H), 2.46 (s, 3H). Calculated m/z for C₁₄H₁₃F₃N₂O m/z:282.1, found m/z=283.0 [M+H]⁺.

Compound 118

R_(f)=0.45 (1:20 MeOH/DCM), purity 98%+. ¹H NMR (300 MHz, Methanol-d₄) δ7.98 (d, J=5.0 Hz, 1H), 7.50-7.42 (m, 2H), 7.35 (dt, J=15.0, 7.0 Hz,3H), 7.07 (d, J=5.0 Hz, 1H), 4.38 (t, J=5.8 Hz, 1H), 3.94 (dd, J=5.8,2.9 Hz, 2H), 2.35 (s, 3H), 2.21 (s, 3H). Calculated m/z for C₁₅H₁₈N₂Om/z: 242.1, found m/z=243.0 [M+H]⁺.

Compound 119

R_(f)=0.45 (1:20 MeOH/DCM), purity 98%+. ¹H NMR (300 MHz, Methanol-d₄) δ7.55-7.11 (m, 7H), 4.68 (s, 1H), 4.52-4.37 (m, 2H), 2.62 (s, 3H), 2.41(s, 3H). Calculated m/z for C₁₅H₁₈N₂O m/z: 242.1, found m/z=243.00[M+H]⁺.

Compound 120

R_(f)=0.46 (1:20 MeOH/DCM), purity 95%+. ¹H NMR (300 MHz, DMSO-d₆) δ9.12 (s, 3H), 8.48 (s, 1H), 7.95-7.55 (m, 3H), 7.44 (m, 3H), 4.81 (s,1H), 4.62-4.37 (m, 2H), 2.64 (s, 3H), 2.45 (s, 3H). Calculated m/z forC₁₅H₁₈N₂O m/z: 242.1, found m/z=243.00 [M+H]⁺.

Compound 121

¹H NMR (499 MHz, CD₃OD) δ 8.32-8.41 (m, 1H), 8.25-8.32 (m, 1H),7.44-7.69 (m, 4H), 7.38 (t, J=7.68 Hz, 2H), 7.28-7.35 (m, 1H), 5.12 (dd,J=3.84, 7.68 Hz, 1H), 4.72-4.79 (m, 2H), 4.29-4.47 (m, 2H), 3.57-3.78(m, 2H), 3.39 (s, 3H); Calculated for C₁₆H₂₀N₂O₂: 272.15 Observed: 273.2[M+H]⁺, 295.3 [M+Na]⁺

Compound 122

R_(f)=0.49 (1:20 MeOH/DCM), purity 98%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.50-7.09 (bm, 7H), 5.10 (s, 1H), 4.18 (s, 2H), 3.81-3.68 (m, 2H), 3.51(s, 2H), 3.29 (s, 3H), 2.61 (s, 3H), 2.43 (s, 3H). Calculated m/z forC₁₈H₂₄N₂O₂ m/z: 300.18, found m/z=301.0 [M+H]⁺.

Compound 123

R_(f)=0.48 (1:20 MeOH/DCM), purity 98%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.44 (s, 1H), 8.29 (s, 1H), 7.80 (s, 1H), 7.39 (m, 5H), 5.12 (s, 1H),4.33 (d, J=5.2 Hz, 2H), 3.61 (m, 4H), 3.38 (s, 3H), 2.48 (s, 3H).Calculated m/z for C₁₇H₂₂N₂O₂ m/z: 286.17, found m/z=287.0 [M+H]⁺.

Compound 124

R_(f)=0.46 (1:20 MeOH/DCM), purity 95%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.37 (s, 1H), 7.91-7.21 (m, 7H), 4.52-4.37 (m, 2H), 4.15-4.01 (m, 2H),3.56-3.41 (m, 2H), 3.28 (s, 3H). Calculated m/z for C₁₇H₁₉F₃N₂O₂ m/z:340.14, found m/z=341.0 [M+H]⁺.

Compound 125

R_(f)=0.48 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, Methanol-d₄) δ7.61-7.05 (m, 7H), 4.71-4.60 (m, 1H), 4.54-4.39 (m, 2H), 3.91-3.52 (m,4H), 3.27 (s, 3H), 2.62 (s, 3H), 2.41 (s, 3H). Calculated m/z forC₁₈H₂₄N₂O₂ m/z: 300.18, found m/z=301.0 [M+H]⁺.

Compound 126

¹H NMR (300 MHz, CD₃OD) δ 4.25 (d, J=10.3 Hz, 1H), 4.32 (d, J=10.3 Hz,1H), 6.60-6.70 (m, 4H), 7.41-7.61 (m, 5H). ESI/MS calculated forC₁₃H₁₄N₂O m/z: 214.1, found m/z=215.0 [M+H]⁺.

Compound 127

¹H NMR (300 MHz, CD₃OD) δ 7.41-7.61 (m, 5H), 6.60-6.70 (m, 4H), 4.70(br. s., 1H), 4.48 (br. s., 1H), 4.32 (br. s., 1H), 3.72-3.45 (m. 2H),3.30-3.42 (m, 2H), 3.28 (s, 3H).

ESI/MS calculated for C₁₆H₂₀N₂O₂ m/z: 272.2, found m/z=273.1 [M+H]⁺.

Compound 128

R_(f)=0.47 (1:20 MeOH/DCM), purity 95%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.52 (d, J=5.1 Hz, 1H), 7.63-7.22 (m, 6H), 6.75 (s, 1H), 4.71-4.63 (m,1H), 4.49-4.34 (m, 2H). Calculated m/z for C₁₄H₁₃F₃N₂O m/z: 282.1, foundm/z=283.00 [M+H].

Compound 129

R_(f)=0.50 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, DMSO-d₆) δ8.80 (s, 3H), 8.44 (d, J=9.6 Hz, 1H), 7.96-7.76 (m, 1H), 7.49 (m, 9H),6.99 (d, J=7.5 Hz, 1H), 4.90 (m, 1H), 4.46 (d, J=5.7 Hz, 2H). Calculatedm/z for C₁₈H₁₇NO m/z: 263.1, found m/z=264.1 [M+H].

Compound 130

R_(f)=0.45 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, Methanol-d₄) δ8.81-8.35 (m, 3H), 7.82 (dd, J=16.8, 10.6 Hz, 3H), 7.63 (d, J=6.5 Hz,4H), 7.56-7.09 (m, 5H), 4.81 (s, 1H), 4.40 (s, 2H). Calculated m/z forC₁₈H₁₇NO m/z: 263.1, found m/z=264.1 [M+H]⁺.

Compound 131

R_(f)=0.52 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, DMSO-d₆) δ8.95 (s, 3H), 8.15 (s, 1H), 7.97 (m, 3H), 7.77 (d, J=8.5 Hz, 1H), 7.57(dd, J=5.7, 3.8 Hz, 2H), 7.01-6.87 (m, 3H), 4.90 (s, 1H), 4.38-4.00 (m,2H), 2.10 (s, 6H). Calculated m/z for C₂₀H₂₁NO m/z: 291.16, foundm/z=292.10 [M+H]⁺.

Compound 132

R_(f)=0.60 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, DMSO-d₆) δ8.87-8.42 (m, 3H), 8.12 (s, 1H), 8.09-7.85 (m, 4H), 7.71 (s, 4H), 7.58(d, J=9.4 Hz, 1H), 4.94 (s, 1H), 4.61 (s, 2H). Calculated m/z forC₂₀H₁₅F₆NO m/z: 399.1, found m/z=400.1 [M+H]⁺.

Compound 133

R_(f)=0.48 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, DMSO-d₆) δ8.83 (s, 3H), 8.14 (s, 1H), 8.06-7.85 (m, 3H), 7.75 (d, J=8.6 Hz, 1H),7.57 (dd, J=6.2, 3.3 Hz, 2H), 7.11 (d, J=7.4 Hz, 2H), 6.95 (d, J=7.5 Hz,1H), 6.85 (t, J=7.0 Hz, 1H), 4.92 (s, 1H), 4.39 (d, J=5.5 Hz, 2H), 2.17(s, 3H). Calculated m/z for C₁₉H₁₉NO m/z: 277.15, found m/z=278.1[M+H]⁺.

Compound 134

R_(f)=0.5 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, DMSO-d₆) δ 8.77(s, 3H), 8.10 (s, 1H), 8.04-7.85 (m, 3H), 7.71 (d, J=8.7 Hz, 1H),7.68-7.48 (m, 3H), 7.39-7.28 (m, 2H), 7.13 (t, J=7.4 Hz, 1H), 4.87 (s,1H), 4.58 (dd, J=9.9, 5.9 Hz, 2H). Calculated m/z for C₁₉H₁₆F₃NO m/z:331.12, found m/z=332.1 [M+H]⁺.

Compound 135

R_(f)=0.50 (1:20 MeOH/DCM), purity 97%+. ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (s, 3H), 8.13 (s, 1H), 8.08-7.85 (m, 3H), 7.75 (dd, J=8.5, 1.7 Hz,1H), 7.57 (dd, J=5.6, 3.8 Hz, 2H), 6.61 (d, J=5.0 Hz, 3H), 4.85 (t,J=6.0 Hz, 1H), 4.51-4.18 (m, 2H), 2.22 (s, 6H). Calculated m/z forC₂₀H₂₁NO m/z: 291.16, found m/z=292.10 [M+H]⁺.

Compound 136

R_(f)=0.57 (9:1 CH₂Cl₂:CH₃OH) ¹H NMR (499 MHz, methanol-d₄) δ 7.57 (d,2H), 7.54-7.43 (m, 3H), 7.07-6.97 (m, 2H), 6.97-6.89 (m, 1H), 4.19-4.11(d, 1H, J=10 Hz), 4.08 (d, 1H, J=10 Hz), 2.20 (s, 6H); m/z calculatedfor C₁₆H₁₈DNO: 242.15. Observed for [M+H]⁺: 243.4.

Compound 137

R_(f)=0.52 (9:1 CH₂Cl₂:CH₃OH); ¹H NMR (499 MHz, methanol-d₄) δ 6.98-7.11(m, 2H), 6.89-6.99 (m, 1H), 3.86-3.96 (m, 1H), 3.77-3.86 (m, 1H), 2.30(s, 6H), 1.44 (s, 3H); m/z calculated for C₁₁H₁₆DNO: 180.14. Observedfor [M+H]⁺: 181.2.

Example 4. Preparation of Enantiomers of Mexiletine

Enantiomers of Mexiletine analogs (Scheme 1 and 2) were prepared byNaBH₄ reduction of the starting ketone A to give the racemic alcohol B.B and N,N′-diisopropyl-carbodiimide were combined (catalyzed by CuCl),heated with (R)-mandelic acid in toluene at 150° C. to afford S-C andR-C, that were separated via chromatography. Each diastereomer washydrolyzed with NaOH_(aq) (MeOH:THF), subjected to Mitsunobu reactionconditions in the presence of phthalimide, and treated with excesshydrazine. Each amine in ether was treated with 4M HCl in dioxane at RTto give HCl salts of the enantiomers (R)-D and (S)-D).

TABLE 1 Substituents for Mexiletine enantiomers in Schemes 1 and 2. R₁R₂ R₃ Da H CF₃ CF₃ Db H CH₃ CH₃ De CH₃ H H Dd CF₃ H H

Ketone A was treated with chiral t-bultylsulfinamide catalyzed byTi(OEt)₄ followed by NaBH₄ reduction led to a mixture of diastereomericsulfinamides separated via chromatography. Treatment of each sulfinamidewith HCl in dioxane followed by treatment with Et₂O gave the individualenantiomers (S)-D and (R)-D.

Chiral Amine (S)-Da.

1H NMR (300 MHz, Chloroform-d) δ 4.52-4.63 (m, 1H), 5.29 (t, J=9.6 Hz,1H), 5.80 (dd, J=5.3, 10.1 Hz, 1H), 7.24-7.26 (m 4H), 7.26-7.31 (s, 2H),7.31-7.49 (m, 3H), 7.58 (d, J=6.6 Hz, 1H), 7.68-7.79 (m, 1H), 7.78-7.89(m, 1H). ESI MS: Calculated m/z for C₁₆H₁₃F₆NO: 349.1 Observed: 350.2[M+H]⁺. 1H NMR of the HCl salt (300 MHz, MeOH-d₄) δ 4.44-4.62 (m, 2H),4.78-4.84 (m, 1H), 7.30-7.95 (m, 8H). [α]54620=−17o (c=0.08; CD3OD).

Chiral Amine (R)-Da.

1H NMR (300 MHz, MeOH-d4) δ 4.44-4.62 (m, 2H), 4.78-4.84 (m, 1H),7.30-7.95 (m, 8H). ESI MS: Calculated m/z for C₁₆H₁₃F₆NO: 349.1Observed: 350.2 [M+H]⁺[α]₅₄₆ ²⁰=+19 o (c=0.08; CD3OD).

Chiral Amine (R)-Db.

¹H NMR (300 MHz, MeOH-d4) δ 2.27 (d, J=0.7 Hz, 6H), 4.18-4.38 (m, 2H),4.73 (dd, J=4.1, 8.4 Hz, 1H), 6.64 (s, 3H), 7.42-7.58 (m, 4H).Calculated m/z for C₁₆H₁₉NO: 241.1 Observed: 242.1 [M+H]⁺. [α]₅₄₆²⁰=−30° (c=0.1; CD₃OD).

Chiral Amine (S)-Db.

¹H NMR (300 MHz, MeOH-d4) δ 2.27 (d, J=0.7 Hz, 6H), 4.18-4.38 (m, 2H),4.73 (dd, J=4.1, 8.4 Hz, 1H), 6.64 (s, 3H), 7.42-7.58 (m, 4H).Calculated m/z for C₁₆H₁₉NO: 241.1 Observed: 242.1 [M+H]⁺. [α]₅₄₆²⁰=+32.3° (c=0.1; CD₃OD).

Chiral Amine (R)-Dc.

¹H NMR (300 MHz, MeOH-d₄) δ 2.27 (s, 3H), 3.44 (s, 2H), 4.26-4.40 (m,1H), 6.83-6.97 (m, 1H), 7.08-7.19 (m, 1H), 7.42-7.60 (m, 2H). Calculatedm/z for C₁₅H₁₇NO: 227.1 Observed: 228.1 [M+H]⁺. [α]₅₈₉ ²⁰=−12° (c=0.1;CD₃OD).

Chiral Amine (S)-Dc.

¹H NMR (300 MHz, MeOH-d₄) δ 2.27 (s, 3H), 3.44 (s, 2H), 4.26-4.40 (m,1H), 6.83-6.97 (m, 1H), 7.08-7.19 (m, 1H), 7.42-7.60 (m, 2H). Calculatedm/z for C₁₅H₁₇NO: 227.1 Observed: 228.1 [M+H]⁺. [α]₅₈₉ ²⁰=+15° (c=0.1;CD₃OD).

Chiral Amine (S)-Dd.

¹H NMR (300 MHz, MeOH-d₄) δ 4.43-4.53 (m, 2H), 4.77 -4.85 (m. 1H),7.09-7.31 (m, 2H) 7.43-7.53 (m, 1H), 7.48-7.67 (m, 1H). Calculated m/zfor C₁₆H₁₉NO: 281.1 Observed: 282.1 [M+H]⁺. [α]₅₈₉ ²⁰=+36° (c=0.15;CD₃OD).

Chiral Amine (R)-Dd.

¹H NMR (300 MHz, MeOH-d₄) δ 4.43-4.53 (m, 2H), 4.77-4.85 (m. 1H),7.09-7.31 (m, 2H) 7.43-7.53 (m, 1H), 7.48-7.67 (m, 1H). Calculated m/zfor C₁₆H₁₉NO: 281.1 Observed: 282.2 [M+H]⁺. [α]₅₈₉ ²⁰=−31° (c=0.15;CD3OD). The enantiomers (i.e., (R)- and (S)-Da-Dd) were examined side byside for pharmacological response in cardiomyocytes derived from IPSCsfrom an LQT3 patient. For Da-Dd, it was observed that compared to the(R)-enantiomer, the (S)-enantiomer generally possessed much greateraction potential shortening. This stereoselective result showedfundamental pharmacological interaction with the cellular target in thecells from the patient cohort. The interaction with the cells possessessignificant stereoselectivity. However, this observation is surprisingand unexpected because the clinically used material (i.e.,(R)-Mexilitene) possesses the opposite apparent (and modest)stereoselectivity as observed for the more pharmacologically potentanalogs described in this Example (i.e., Da to Dd). Further, (R)- and(S)-Mexilitene itself does not show significant stereoselectivity forshortening of the action potential in IPSCs-derived cardiomyocytes froman LQT3 patient (i.e., (R)-Mexilitene ratio is 1.3 and (S)-Mexilitene is1.25 and racemic Mexilitene ratio is 1.3, see Table 3, Example 1, datafor entries 1, 2a and 2b). This result may be due to the differences inthe pharmacological preparations used in the experiments.

Example 5: Separation of Enantiomers of Mexiletine

Reverse phase HPLC analysis. RPHPLC analysis of N-tert-butanesulfinylamine derivatives of Mexiletine and analogs (Example 4, Scheme 2) wasdone on a Hitachi HPLC using a Phenomenex Luna C18 column (5 μm, 150×4.6mm) using gradient elution at a flow rate of 1.0 mL/min. Compounds wereeluted using a mobile phase gradient of 60/40 water/acetonitrile with0.05% TFA to 20/80 water/acetonitrile with 0.05% TFA. UV detection wasat 254 nm.

Chiral Phase HPLC Analysis.

Mexiletine enantiomers and enantiomers of analogs were analyzed by HPLCon a Hitachi HPLC using a Phenomenex Lux Cellulose-1 column (5 m,150×4.6 mm) with isocratic elution using a mobile phase of 75/20/5hexanes/isopropanol/acetonitrile with 0.01% perchloric acid (70% aqueoussolution) at a flow rate of 0.75 mL/min. UV detection was at 220 nm. Onthe basis of chiral phase HPLC, purity of Mexiletine enantiomers wasobserved to be >95%. Purity of synthetic Mexiletine analog enantiomers(RPHPLC) was observed to be >95%.

Example 6: Synthesis of Deuterated Compounds for Improved MetabolicStability

Deuterated compounds 104a-d were synthesized according to Scheme 1(below). Ketones 101a-101d were treated with NaBD₄ (>99% deuterium) inEtOH at RT to afford deutero alcohols 102a-102d that were treated withphthalimide, triphenylphosphine and diisopropyl azodicarboxylate in THF(72 h) to provide 103a-103d. Treatment of 103a-103d with hydrazinehydrate in refluxing EtOH (20 h) yielded the free base form of theamines that were converted to their corresponding HCl salts 104a-104d bytreatment with HCl in dioxane/ether (1 h, RT).

TABLE 1 Deuterated Analogs of Mexiletine Analogs Compd R₁ R₂ R₃ 104 a HCF₃ CF₃ 104 b H CH₃ CH₃ 104 c CH₃ H H 104 d CF₃ H H

Compound 104a

(R₁═H; R₂═CF₃; R₃═CF₃): ¹H NMR (300 MHz, MeOH-d₄) δ 4.48 (d, J=10.4 Hz,1H), 4.55 (d, J=10.4 Hz, 1H), 7.42-7.59 (m, 4H), 7.61-7.65 (m, 4H).ESI/MS calcd. for C₁₆H₁₂DF₆NO m/z=350.1, found m/z=351.0 [M+H]⁺.

Compound 104b

(R₁═H; R₂═CH₃; R₃═CH₃) ¹H NMR (300 MHz, MeOH-d₄) δ 2.27 (s, 6H), 4.25(d, J=10.3 Hz, 1H), 4.32 (d, J=10.3 Hz, 1H), 6.64 (s, 3H), 7.41-7.61 (m,5H). ESI/MS calcd. for C₁₆H₁₈DNO m/z: 242.1, found m/z=243.00 [M+H]⁺.

Compound 104c

(R₁═CH₃; R₂═H; R₃═H): ¹H NMR (300 MHz, MeOH-d₄) δ 2.27 (s, 3H), 4.34 (m,2H), 6.77-7.01 (m, 2H), 7.02-7.30 (m, 2H), 7.30-7.76 (m, 2H). ESI/MScalcd. for C₁₆H₁₈DNO m/z: 228.1, found m/z=229.0 [M+H]⁺.

Compound 104d

(R₁═CF₃; R₂═H; R₃═H): ¹H NMR (300 MHz, MeOH-d₄) δ 4.47 (broad m, 2H),7.09-7.20 (m, 1H), 7.24 (d, J=8.2 Hz, 1H), 7.34-7.69 (m, 7H). ESI/MScalculated for C₁₅H₁₃DF₃NO m/z: 282.1, found m/z=283.0 [M+H]⁺.

Because a prominent route of metabolism of Mexilitene and analogsinvolves C—H oxidation (alpha to the amine), replacement of the labileC—H bond with C-D decreases metabolism, decreases clearance andincreases bioavailability and efficacy (also, see Example 15, below).

In biological testing in cardiomyocytes derived from IPSCs from an LQT3patient, it was observed that compared to unlabeled compound,deuterium-labeled Mexilitene analogs (e.g., 104a and 104b) showed equalto or greater action potential shortening (Table 1). This resultillustrates that deuterium labeling at the alpha position does notchange the fundamental pharmacological interaction with the cellulartarget. However, a kinetic isotope effect on metabolism and decreasedclearance of the molecule will be manifested in vivo to improvebioavailability and further improve efficacy.

TABLE 1 Effect of Deuterated and Non-Deuterated Mexilitene Analogs onCardiomyocytes. LQT- WT-EC₅₀ WT-Cess. WT- LQT-EC₅₀ Cess. LQT- LQT- (μM)Dose Prolong. (μM)- Dose Fold Shortening CPD^(a,b) Structure -Prolong.(μM) Dose (μM) Shortening (μM) Shortening Dose (μM) 78 bis-CF₃ No AP 133No AP 23.08 66 1.208 22 racemic parent prolongation Prolong. 104abis-CF₃ No AP 66 No AP No AP 133 1.274 22 Deuterated prolongationProlong. shortening 82 mono-CF₃ No AP 66 No AP 4.07 66 1.539 22 racemicparent prolongation Prolong. 104d mono-CF₃ No AP 22 No AP (no 66 1.39522 Deuterated prolongation Prolong. EC50-but shortens) 25 mono-CH₃ 1247No EADs 4.07 996.9 1.539 1.606 22 racemic parent 104c mono-CH₃ No AP 66No AP No AP 22 No AP No AP Deuterated prolongation Prolong. shorteningshortening shortening 70 bis-CH₃ No AP 66 No AP <0.8 66 1.279 7.4racemic parent prolongation Prolong. 104b bis-CH₃ No AP 22 No AP 0.87 221.280 2.5 Deuterated prolongation Prolong. ^(a)No EADs or Spiky Peaksfor any compound; ^(b)No AP Prolongation for any compound

Example 7: Synthesis of Compounds of Formula III

The pyridinoxy propan-2-amine-based compounds (i.e., 2, 3 or4-pyridin-ol Mexiletine analogs) of general formula III were synthesizedaccording to the Schemes in Example 3.

Example 8. Metabolic and Chemical Stability

Metabolic Stability Studies in the presence of Rat, Mouse or Human LiverMicrosomes or S9.

A typical incubation contained rat, mouse, dog or human liver microsomes(0.4-0.5 mg of protein), 100 mM potassium phosphate buffer (pH7.4), 50μM test compound, an NADPH-generating system consisting of 0.5 mM NADP⁺,0.5 mM glucose-6-phosphate, 1 IU/mL glucose-6-phosphate dehydrogenase, 1mg/mL diethylenetriaminepentaaceticacid (DETAPAC), and 3 mM MgCl₂ in afinal incubation volume of 0.25 mL. Incubations were run for 0, 7, 15,30, and 60 min with constant shaking at 37° C. in a water bath and wereterminated by the addition of 0.75 mL cold ACN. After centrifugation at3000 rpm for 5 min, the organic fraction was collected, the solvent wasremoved with a stream of argon and the residue was reconstituted in 125μL of MeOH and 125 μL H₂O, mixed thoroughly, centrifuged at 13,000 rpmfor 5 min and analyzed by high performance liquid chromatography.Samples were run on a Hitachi D-7000 HPLC system using a L-7100analytical pump, L-7400 UV-Visible variable wavelength detector, andL-7600 automatic sample injector. A Gemini C18 column (250×4.6 mm, 5 umparticle size; Phenomenex,) with a C18 guard column were used forchromatographic separation of the Mexiletine analogs. The mobile phasewas an isocratic system using 75% water (0.05% TFA) and 25% acetonitrile(0.05% TFA) with a flow rate of 1.25 mL/min monitored at 275 nm.Disappearance of the analyte was monitored over time. A plot of the areaunder the curve for the normalized analyte versus time afforded thehalf-life values and k_(app).

TABLE 1 Metabolic Stability of 25, 70, 78 and 82 in Human, Dog, Mouseand Rat Liver microsomes. Liver Microsomes t_(1/2) (min) Compound HumanDog Mouse Rat

104 184  59  52

Stable >95% parent after 60 min 116 Stable >95% parent after 60 minStable >95% parent after 60 min

141 Stable >95% parent after 60 min 208 475

Stable >95% parent after 60 min Stable >95% parent after 60 min 196 198

The Mexiletine analogs tested (Table 1, above) showed surprisingstability in the presence of microsomes that efficiently metabolizedtestosterone. This is attributed to replacement of the metabolicallylabile 2,6-dimethyl groups of Mexiletine with metabolically stable CF3-or H-moieties. Unexpectedly, movement of the dimethyl group to the3,5-position also resulted in a compound that was relatively stableshowing the microsomal oxidase(s) that oxidize Mexiletine at the2,6-dimethyl positions do not efficiently oxidize analogs withsubstitutions at the 3,5-position. Moving the substituents from the2,6-positions to the 3,5-positions improves planarity and decreasesmetabolism. Molecular energy minimization (Avogadro software) ofMexiletine and analogs showed the key dihedral angle of Mexiletine(20.7°) and showed lack of planarity due to an aryl 2,6-dimethyl “gemdimethyl” effect. In contrast, 3- or 5- or 3,5-disubstituted compoundsshowed a 0° dihedral angle. We hypothesize that 3, 5-aryl-mono ordi-substituted Mexiletine analogs possess greater on-target potency anddecreased arrhythmogenicity and decreased hepatic microsomal metabolismand better bioavailability.

TABLE 2 STABILITY OF LEAD COMPOUNDS IN S9 FRACTIONS % Metabolism %Metabolism % Metabolism % Metabolism Compound Human S9 Rat S9 Dog S9Mouse S9

41.1 ± 28.9 2.1 ± 1.4 25.6 ± 17.9 11.6 ± 3.0 

39.2 ± 8.4  45.0 ± 14.5 35.8 ± 7.0  13.6 ± 5.0 

7.0 ± 0.1 97.8 ± 19.5 98.0 ± 28.1 34.6

28.0 ± 7.4  15.4 ± 10.5 51.0 ± 19.1 55.0 ± 22.4

Metabolism of Mexiletine analogs in the presence of hepatic S9 from rat,mouse, dog or human (0.5 mg of protein) were conducted as above andanalyzed by HPLC as described above. With the possible exception of 25(in the presence of rat or dog liver S9), the Mexiletine analogs wererelatively stable in the presence of S9 (Table 2). Microsomes containCYPs and FMO metabolic enzymes. S9 contains soluble enzymes (i.e.,aldehyde oxidase, MAO, etc.). The data suggests that, unexpectedly, thepresence of F-containing substituents decreases metabolism at distalsites due to metabolism by S9 enzymes.

Stability of Mexiletine Analogs at Various Temperatures and pH.

A typical incubation contained 100 μM of the test compound prepared inPBS buffer (pH 7.4 or 3.0, 50 mM) with 1% Ethanol. The test compoundswere incubated at 37° C. An aliquot from incubations was taken atvarious times and injected onto an RP-HPLC system as described above.Disappearance of the analyte was monitored over time. A plot of the areaunder the curve for the normalized analyte versus time afforded thehalf-life values and kapp.

TABLE 3 Chemical stability results for Mexiletine Analogs. Half-Life @Half-Life @ pH 7.4 and pH 3.0 and Compound 37° C. 37° C.

stable > 30 days^(a) stable > 30 days^(a)

t_(1/2) = 30 days stable > 30 days^(a)

stable > 30 day^(a) stable > 15 days^(a)

stable > 30 days^(a) stable > 15 days^(a) ^(a)No observed change in theparent peak compared to time zero by HPLC analysis.

Chemical stability of the Mexiletine analogs was apparent at pH 7.4 andpH 3 that mimicked the pH of serum and the contents of the gut,respectively (Table 3). The results showed no autooxidation, hydrolysisor other degradation is occurring and the compounds are remarkablystable for extended periods of time (>30 days).

Example 9: In Vivo Studies with Mexilitene Analogs

A prominent adverse reaction in the patient cohort (and others reportedin the literature) administered (R)-Mexilitene is nausea and seizures.Because Mexilitene analogs (e.g., 25, 69, 70, 78, 82, 88, 105) possessedLog P values (i.e., 3.2, 4.1, 3.7, 4.5, 2.3, 1.9 and 4.0, respectively)and total polar surface area (PSA Å² values of 35, 30, 35, 35, 35, 47and 40, respectively) showing lipophilic and blood brainbarrier-penetrating properties, we compared the behavioral properties ofthe compounds and compared them to Mexilitene. It is known thatcompounds with PSA less than 60 Å² and molecular weight below 450 (bothobserved for the Mexilitene analogs described herein) possess very goodGI absorption properties and good CNS-absorption (to treat CNSdiseases). Male BALBc mice (20-22 g) were used throughout these studies.The animals were maintained in a temperature-controlled room with 12-hrperiods of light and darkness and had continuous access to water andanimal food. Mexiletine or Mexiletine analogs showed good watersolubility and were dissolved in 10:30:60% DMSO:PEG400:water (v:v) andadministered via i.p. injection (5 ml/kg). Groups contained 2-4 animals.Compound treatment was: vehicle or Mexiletine (30 or 100 or 200 mg/kg)or Mexiletine analogs (30 or 100 or 200 mg/kg) administered andmonitored for 24 hr after treatment. HBRI compounds (25, 36, 69, 70, 78,82, 88 or 105) possessed good solubility and were well-tolerated (30-100mg/kg). For (R)- or (S)- or Racemic Mexiletine, administration of 30mg/kg produced lethargy and in some cases immobilization. At greaterdoses (100 or 200 mg/kg), (R)- or Racemic Mexiletine produced seizuresand death. (S)-Mexiletine (200 mg/kg) produced lethargy, immobilizationand death but severe seizures were not observed. In contrast, micetreated with HBRI compounds 36, 69, 70, or 88 (200 mg/kg) only showedslight lethargy. All behavioral effects subsided after ˜45 mins andanimals recovered to full activity after 2-3 hours. Both Mexiletineanalogs tested and Mexiletine (R->Racemate>S-) produced apparentincrease in fast heart rate effects that subsided with time. Inconclusion, it was apparent that the Mexiletine analogs testedshowedconsiderably less toxicity (i.e., lack of seizures and death) whilepreserving cardiovascular effects observed for Mexiletine. The lack ofCNS and peripheral (i.e., muscle) toxicity shows that the compounds haveutility for CNS diseases such as seizures and epilepsy and otherchannelopathies.

Example 10: Electrophysiology Studies with Mexilitene Analogs

The basis for LQT3 is a mutation in SCN5a that encodes the voltage-gatedNa channel responsible for cardiac action potential. The Na current(I_(Na)) has peak and late components: the peak component initiates theaction potential but as voltage rises, the channel normally inactivates.The late current is normally a very small portion of the channels thatdo not inactivate. The LQT3 mutation impairs inactivation. The latecomponent is then enlarged, resulting in action potential prolongation.We identified compounds that more potently and selectively blocked thelate current (I_(NaL)) in LQT3 patient-derived iPSC-cardiomyocytes.Whole cell patch clamp electrophysiology experiments in LQTS3cardiomyocytes helped determine the functional activity of drugcandidates for inhibition of the late sodium current in the cells. Thus,we tested compounds for Peak (I_(NaP)) and Late (INaL) components. Theywere recorded in a “whole-cell” voltage-clamp mode configuration inresponse to voltage stimulation steps from −80 mV to +40 mV and theirIC₅₀ values determined (Table 1). Table 1 is a summary table with theIC₅₀ values for peak sodium current (I_(NaP)) inhibition, late sodiumcurrent (I_(NaL)) inhibition and the ratio of the IC₅₀ for I_(NaP)inhibition to the IC₅₀ for I_(NaL) inhibition. The Peak/Late ratio for25, 82, 36 and 70 was 60 to 316-fold. This value is similar or greaterto that observed measuring the effect on Na ion channels overexpressedin CHO cells (overexpressed Na_(v)1.5 encoded by the LQT3 mutated SCN5A)as presented in Table 1, Example 2, above. Mexiletine has a Peak/Lateratio of ˜3. Thus, based on electrophysiology results, our approach ofusing patient-specific cells has succeeded quite well in producing drugcandidates that are much more selective for INaL.

TABLE 1 Effect of Mexiletine Analogs on Electrophysiology in TransfectedCHO Cells. Ratio Mex^(a) Ratio of Mex IC₅₀ for IC₅₀ for RatioI_(NaL)/Lead Ratio/Lead Compound I_(NaP) (μM) I_(NaL) (μM)I_(NaP)/I_(NaL) I_(NaL) Ratio^(b) Mexiletine 145 51 2.7 N/A N/A 25 1021.7 60 30 22.3 82 200 1.8 111 28.3 41 36 51.8 0.38 136 134.2 50 70 1710.54 316 94.4 117

The peak current (INaP) mediates cardiac excitability and is anundesired effect of the molcules. Potency at the late current (I_(N)a)is the desired goal. The ratio of the two indicates the selectivity andthe IC₅₀ indicates the potency of the molecules. Drug candidate (e.g.,36) is as much as 134-fold more potent than racemic mexiletine. Compound70 is as much as 117-fold more selective than mexiletine. Both metricsshow that we have developed significantly more potent and selectiveinhibitor of I_(NaL) that could be used for the treatment of LQT3 orother indicitions where I_(NaL) inhibition is the therapeutic target.

Example 11: Metabolism Studies with Mexilitene Analog Enantiomers

Racemic 25, 82, 70 and 78 possessed metabolic stability (in livermicrosomes of T_(1/2)>60 mins) and chemical stability (T_(1/2)>30 days,pH 7.4, 37° C.) (see Example 8). Using the HPLC method described inExample 8, testing metabolism of drug candidate enantiomers showed goodmetabolic stabililty. Metabolism of Mexiletine and drug candidates wasconducted in human liver S-9 and microsomes, respectively. In goodagreement with the literature, Mexiletine was not metabolized veryextensively (Table 1). In the presence of S-9, 25, 36 and 70 weredetectably metabolized as judged by HPLC. Metabolism was stereoselectivewith the (R)-enantiomer metabolized greater than the (S)-enantiomer(Table 1). In the presence of human liver microsomes, compounds 82, 70and 36 were metabolized as judged by HPLC. In good agreement with S-9studies (above) metabolism was stereoselective, with the (R)-enantiomergreater than the (S)-enantiomer (Table 1).

TABLE 1 Metabolic Stability of Mexiletine and Analogs with Human LiverPreparations Compound # Liver S-9 T_(1/2) Liver Microsomes T_(1/2)(S)-82 >95% after 1 hr 365 minutes (R)-82 >95% after 1 hr 136 minutes(R)-25 408 minutes >95% after 1 hr (S)-25 >95% after 1 hr >95% after 1hr (R)-70 1015 minutes 406 minutes (S)-70 >95% after 1 hr >95% after 1hr (S)-36 >95% after 1 hr >95% after 1 hr (R)-36 187 minutes 175 minutes(R)-78 >95% after 1 hr >95% after 1 hr (S)-78 1040 minutes >95% after 1hr (R)-Mexiletine >95% after 1 hr >95% after 1 hr (S)-Mexiletine >95%after 1 hr >95% after 1 hr

It is known that certain CYPs (i.e., CYP3A4 and CYP2D6) play a role inthe metabolism of Mexiletine. Accordingly, we examined the metabolism ofleads with highly purified CYPs with an HPLC method (Example 8). Asshown in Table 2, compared to Mexiletine, minor CYP-dependent metabolismwas observed for 82 and 70. The data show analogs 82, 36 and 70 are moremetabolically stable than Mexiletine in the presence of highly purifiedCYP 450. Unexpectedly, Mexiletine was metabolized by FMO (Example 16).It is known that FMO metabolizes primary amines but it was unknown thatFMO metabolizes Mexiletine.

TABLE 2 Metabolic Stability of Mexiletine and Rac Compounds with HumanLiver Cytochrome P-450a nmols nmols/μg pmols product/μg metabolized CYPCYP/min Mexilitene CYP3A4 32.4 2.31 46.2 CYP3A5 34.2 2.44 48.8 CYP2D64.04 0.3 6.0 Rac 82 CYP3A4 10.9 0.77 15.4 CYP3A5 29.9 2.13 42.6 CYP2D629.1 2.18 43.6 Rac 36 CYP3A4 ND^(b) ND CYP3A5 ND ND CYP2D6 ND ND Rac 70CYP3A4 ND ND CYP3A5 ND ND CYP2D6 4.6 .345 6.92 ^(a)50 min incubation,ND, ^(b)Not Detectable

Example 12: Behavioral and Safety Studies with Mexilitene AnalogEnantiomers

Safety has been established in several enantiomers of drug candidates.The literature states the LD₅₀ for Mexiletine in mice is 114 mg/kg.Administration of 200 mg/kg for 25, 82, 70, or 36 enantiomers did notshow any lethality. Thus, the LD₅₀ is >200 mg/kg for these compounds. Incontrast, lethality was observed for Mexiletine at 100 and 200 mg/kg.Thus, the drug candidates examined are safer than Mexiletine.

A prominent adverse reaction in the patient cohort (and others reportedin the literature) administered (R)-Mexiletine is nausea and seizures.We compared the behavioral properties of enantiomerically pure drugcandidates (i.e., 25, 82, 70, 78 and 36) and compared them to (R)- or(S)-Mexiletine at 100 mg/kg (Table 1). Drug candidate enantiomers (i.e.,enantiomers of 25, 82, 70, 78 and 36) were well-tolerated in vivo (100mg/kg) in terms of behavioral effects (or lack thereof). In contrast,for (R)-Mexiletine, administration of 100 mg/kg produced immobilization,seizures and death. (S)-Mexiletine (100 mg/kg) produced lethargy andimmobilization but severe seizures were not observed. In contrast, micetreated with drug candidate enantiomer (R)-82, 70, or 78 (100 mg/kg)unexpectedly showed no apparent behavioral effects. Minor lethargy wasobserved for (S)-25, 82, 70 and 78. Thus, adverse behavioral effectswere stereoselective (adverse effects S->R-). In conclusion, compared toMexiletine, it was apparent that (R)-enantiomer drug candidate compoundsexamined showed considerably less toxicity (i.e., seizures and death)than that observed for Mexiletine enantiomers.

TABLE 1 Effect of Stereochemistry on Behavioral Effects of MexiletineAnalogs. Behavior Effect^(a) Behavior Effect^(a) Compound (R)-enantiomer(S)-enantiomer 82 No detectable effect 2/4 slightly lethargic 70 Nodetectable effect 2/4 lethargic 78 No detectable effect 2/4 shaking 363/4 immobilized No detectable effect 25 4/4 immobilized 3/4 immobilizedMexilitene 1 seizure, 1 death, 4/4 immobilized 2 immobilized

Example 13: Effect of Pyridyl-Mexiletine Derivatives on WT and LQT-3Cardiomyocytes

Pyridyl-Mexiletines moderate potency for LQT-3 shortening. Two mosteffective compounds, (i.e., unsubstituted 4-pyridyl (i.e., 126) andortho-methyl-3-pyridyl compounds (i.e., 111), showed shortening EC50values of approximately 4 and 8 μM, respectively. The unsubstituted3-pyridyl derivative (i.e., 121) with the N-methoxy ethyl modificationalso showed moderate shortening in LQT-3 cells (Table 1).

TABLE 1 Effect of Pyridyl-Mexiletine derivatives on WT and LQT-3Cardiomyocytes. WT-EC₅₀ LQT-EC₅₀ LQT- LQT- Compound (μM) WT-Cessation(μM) Fold Shortening Number Structure Prolongation Dose (μM) ShorteningShortening Dose (μM) 19

Does Not Prolong AP 133 1.38 1.406  66 20

Does Not Prolong AP No cessation of beating Does Not Shorten Does NotShorten Does Not Shorten 48

Does Not Prolong AP No cessation of beating Does Not Shorten Does NotShorten Does Not Shorten 94

18.48 No cessation of beatimg 12.82 1.287  66 96

Does Not Prolong AP No cessation of beating 20.7 1.358 133

TABLE 2 Effect of 3-Pyridyl-Mexiletine derivatives on WT and LQT-3Cardiomyocytes WT-EC₅₀ WT- LQT-EC₅₀ LQT- Compound (μM) Cessation (μM)LQT-Fold Shortening Number Structure Prolongation Dose (μM) ShorteningShortening Dose (μM) 110

33.76 No cessation of beating 62.56 (Prolongation and EADs) 1.546(Prolongation) 133 111

Does Not Prolong AP 133 8.57 1.426 Does Not Shorten 112

19.4 No cessation of beating Does Not Shorten Does Not Shorten Does NotShorten 113

7.24 200 Does Not Shorten Does Not Shorten Does Not Shorten 114

Does Not Prolong AP No cessation of beating 67.5 1.233 22 115

25.7 No cessation of beating Does Not Shorten Does Not Shorten Does NotShorten 116

Does Not Prolong AP 200 Shortens 1.422 22 117

Does Not Prolong AP  66 Does Not Shorten Does Not Shorten Does NotShorten 118

8.22 No cessation of beating Does Not Shorten Does Not Shorten Does NotShorten 119

Does Not Prolong AP No cessation of beating Shortens 1.123 22 120

7.33 No cessation of beating Does Not Shorten Does Not Shorten Does NotShorten 121

25.42 No cessation of beating 2.58 1.144 22 122

Does Not Prolong AP 200 46.57 1.188 66 123

Does Not Prolong AP 200 Shortens 1.402 66 124

Does Not Prolong AP  66 Shortens 1.601 7.4 125

Does Not Prolong AP  66 Does Not Shorten Does Not Shorten Does NotShorten

TABLE 3 Effect of 4-Pyridyl-Mexiletine derivatives on WT and LQT-3Cardiomyocytes WT-EC₅₀ WT- LQT-EC₅₀ LQT- LQT- Compound (μM) Cessation(μM) Fold Shortening Number Structure Prolongation Dose (μM) ShorteningShortening Dose (μM) 126

Does Not Prolong AP No cessation of beating 3.82 1.281 7.4 127

97.68 No cessation of beating Does Not Shorten Does Not Shorten Does NotShorten 128

Does Not Prolong AP No cessation of beating Shortens 1.226 22

Example 14: Naphthalene Derivatives of Mexiletine and Analogs

Naphthalene derivatives of Mexiletine and several lead compounds bearingphenol substitution were synthesized following the previously describedmethod (Scheme 1, Example 3) and obtained in good yield and excellentpurity. Naphthalene analogs of Mexiletine and the lead compounds showedpotency with significant LQT-3 shortening. Although the shortening EC₅₀was generally greater than the corresponding phenyl analogs, thecessation dose was also increased. The most potent bicyclic compoundtested contained 1-naphthol as a phenol moiety analog, consistent withthe hypothesis that this would be highly potent given the structuralsimilarity to analogs with 2,3-dimethyl phenol substituents (e.g.,30-36). Although showing some prolongation effects in wild type cells,the mono-trifluoromethyl naphtha-Mexiletine compound (i.e., 134) washighly potent and did not induce cessation of beating at theconcentrations examined.

TABLE 1 Effect of Naphtha-Mexiletine derivatives on WT and LQT-3Cardiomyocytes. WT-EC₅₀ LQT-EC₅₀ LQT- LQT- LQT- Compound (μM) (μM)Cessation Fold Shortening Number Structure Prolongation Shortening Dose(μM) Shortening Dose (μM) 129

Does Not Prolong AP 0.82  66 1.316 2.5 130

Does Not Prolong AP 8.7 133 1.459 66 131

Does Not Prolong AP 4.73 133 1.309 22 132

Does Not Prolong AP Shortens No cessation of beating 1.205 133 133

Does Not Prolong AP 8.83 133 1.302 22 134

24.40 1.79 No cessation of beating 1.515 133 135

Does Not Prolong AP Shortens 200 1.667 133

Example 15: Metabolism of Deuterated Mexiletine Analogs

As discussed above (Example 6), deuterated Mexiletine analogs weresynthesized and tested in hepatic preparations or enzymes to determineif deuteration would decrease metabolism compared to Mexiletine.Compared to Mexiletine, data of Table 1, below, shows that thedeuterated analogs were in general, more metabolically stable. In manycases, an apparent large isotope effect is apparent for the deuteratedcompounds compared to non-deuterated Mexiletine.

TABLE 1 Effect of Metabolism on Deuterated Analogs and unlabeledMexiletine. Mouse Human Human Human liver S-9 FMO1 FMO3 CYP3A4 Compound(nmol/incub)^(a) (nmol/incub)^(b) (nmol/incub)^(b) (nmol/incub)^(c)Mexiletine 5.2 6.7 ND^(d) 3.0 104a ND^(d) 0.8 0.6 1.1 104c 13.2 1.4 1.31.0 104d ND 0.3 0.7 0.3 104b ND 1.0 0.05 0.3 ^(a)0.4 mgprotein/incubation; ^(b)15 μg enzyme/incubation; ^(c)3 pmolenzyme/incubation; ^(d)ND, no detectable decrease. Incubations were runfor 30 mins with shaking at 37° C. Expressed as nmolmetabolism/incubation.

As a further example, the metabolism of Mexiletine was compared todeuterated Mexiletine (135) and Phenyl Mexiletine was compared withdeuterated Phenyl Mexiletine (136), (compounds in Example 3). As shownin Table 2, generally, compounds with deuterium (i.e., 135 and 136)showed large and unexpected isotope effects on metabolism. This willtranslate to a large isotope effect on in vivo metabolism, a decrease inclearance, greater bioavailability and longer efficacy. This will resultin a more long-lived human drug resulting in fewer doses/day and lessside effects and greater efficacy.

TABLE 2 Effect of Metabolism on Deuterated Mexiletine and PhenylMexiletine. Condition D^(d)- Phenyl D^(d)-Phenyl Mexiletine MexiletineMexiletine Mexiletine nmol nmol nmol nmol metab./ metab./ metab./metab./ incub. incub. incub. incub. Mouse S-9^(a) 8.0 3.9 2.5 1.4 HumanS-9^(a) 3.9 2.7 1.2 1.4 Human FMO1^(b) 2.4 1.4 0.33 0.06 HumanCYP3A4^(c) 4.1 5.2 2.3 1.5 ^(a)0.4 mg protein/incubation; ^(b)15 μgenzyme/incubation; ^(c)3 pmol enzyme/incubation; Incubations were runfor 30 mins with shaking at 37° C. and results are in nmol ofmetabolism/incubation, ^(d)D stands for deuterium.

Example 16. Effect of (R)-82 on an Aged Rat Heart Perfusion Model ofArrhythmia

Conduction velocity (CV), action potential duration (APD) andresponsiveness to drugs was measured in ex-vivo rat heart preparations(FIG. 1). We chose a rat heart model to test for the effect of (R)-82(i.e., (R)-Dd, Example 4) to decrease arrhythmias because CV and APD arepreserved in buffer-perfused rat hearts up to 2 days. In contrast, inthis model, continuous presence (perfusion) of H₂O₂ (0.1 mM) producesearly after depolarizations (EADs) and ectopic ventricular beats 6 minafter exposure that degenerates to ventricular tachycardia (VT) andventricular fibrillation (VF) after 12 min (FIG. 1). Left untreated, theheart would die within 45 mins. Using this preparation, completeresolution of all forms of arrhythmias to normal sinus rhythm wasobserved 30 min after perfusion of compound (R)-82 (10 VM) in thecontinuous presence of H₂O₂ (0.1 mM) (FIG. 2). This shows thatadministration of (R)-82 (i.e., (R)-Dd, Example 4) to a heart sufferingfrom severe arrhythmias potently reverses VT and VF and corrects EADs ina very clinically relevant short time. The effect of (R)-82 is similarto or more potent than the effect of ranolazine (10 M) in the same exvivo model. The conclusion is that (R)-82 is more efficacious than thecurrently used standard of care.

1. A compound of Formula I:

or a stereoisomer, tautomer, isotope, or salt thereof, wherein: A, B, Dare independently Carbon or Nitrogen; R₁ is selected from the groupconsisting of methyl, trideuteromethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,phenyl, (C₆-C₂₄)aryl, and (C₅-C₂₄)heteroaryl, wherein (C₆-C₂₄)aryl and(C₆-C₂₄)heteroaryl are optionally substituted with 1 to 5 R₈substituents, in particular, 1 or 2 R₈, independently selected from thegroup consisting of deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl; R₁′ is selected from the group consisting ofhydrogen and deuterium; R₂ is selected from the group consisting ofhydrogen, deuterium, methyl, trideuteromethyl, trifluoromethyl,2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloheteroalkyl, 2-(C₁-C₆)alkoxyethyl, 2-hydroxyethyl,2-(C₆-C₂₄)aryloxyethyl, bis(2-methoxyethyl), (C₁-C₆)alkoxymethyl,2-(C₃-C₆)cycloalkoxyethyl, (C₆-C₂₄)aryl, and (C₆-C₂₄)heteroaryl, wherein(C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl are optionally substituted with 1 to5 R₈ substituents selected from the group consisting of deuterium, halo,methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino,cyano, nitro and and (C₁-C₆)alkylsulfonyl; R₃ is absent if A isNitrogen, or if A is Carbon, R₃ is selected from the group consisting ofhydrogen, deuterium, halo, methyl, trideuteromethyl, trifluoromethyl,2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy,(C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,(C₆-C₂₄)arylamino, cyano, nitro, and (C₁-C₆)alkylsulfonyl; R₄ is absentif B is Nitrogen, or if B is Carbon, R₄ is selected from the groupconsisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl; R₅ is absent if D is Nitrogen, or if D is Carbon,R₅ is a substituent selected from the group consisting of hydrogen,deuterium, halo, methyl, trideuteromethyl, trifluoromethyl,2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy,(C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,(C₆-C₂₄)arylamino, cyano, nitro, and (C₁-C₆)alkylsulfonyl; R₆ and R₇ areindependently selected from the group consisting of hydrogen, deuterium,halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino,cyano, nitro, and (C₁-C₆)alkylsulfonyl; and wherein the indicated (*)carbon is in the R- or S-configuration.
 2. The compound of claim 1wherein the compound is of Formula Ia:

or a stereoisomer, tautomer, isotope, or salt thereof, wherein: R₁ isselected from the group consisting of methyl, trideuteromethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, phenyl, (C₆-C₂₄)aryl, and(C₅-C₂₄)heteroaryl, wherein (C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl areoptionally substituted with 1 to 5 R₈ substituents, in particular, 1 or2 R₈, independently selected from the group consisting of deuterium,halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino,cyano, nitro, and (C₁-C₆)alkylsulfonyl; R₁′ is selected from the groupconsisting of hydrogen and deuterium; R₂ is selected from the groupconsisting of hydrogen, deuterium, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloheteroalkyl, 2-(C₁-C₆)alkoxyethyl, 2-hydroxyethyl,2-(C₆-C₂₄)aryloxyethyl, bis(2-methoxyethyl), (C₁-C₆)alkoxymethyl,2-(C₃-C₆)cycloalkoxyethyl, (C₆-C₂₄)aryl, and (C₆-C₂₄)heteroaryl, wherein(C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl are optionally substituted with 1 to5 R₈ substituents, in particular, 1 or 2 R₈, selected from the groupconsisting of deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro and(C₁-C₆)alkylsulfonyl; and R₃, R₄, R₅ and R₆ are independently selectedfrom the group consisting of hydrogen, methyl and trifluoromethyl. 3.The compound of claim 2 wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 4. The compound of claim 2wherein the compound is:

or a stereoisomer or isotope or salt thereof.
 5. The compound of claim 1wherein the compound is of Formula Ib:

or a stereoisomer, tautomer, isotope or salt thereof, wherein: R₁ isselected from the group consisting of methyl, trideuteromethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, phenyl, (C₆-C₂₄)aryl, and(C₅-C₂₄)heteroaryl, wherein (C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl areoptionally substituted with 1 to 5 R₈ substituents, in particular, 1 or2 R₈, independently selected from the group consisting of deuterium,halo, methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino,cyano, nitro, and (C₁-C₆)alkylsulfonyl; R₁′ is selected from the groupconsisting of hydrogen and deuterium; R₂ is selected from the groupconsisting of hydrogen, deuterium, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloheteroalkyl, 2-(C₁-C₆)alkoxyethyl, 2-hydroxyethyl,2-(C₆-C₂₄)aryloxyethyl, bis(2-methoxyethyl), (C₁-C₆)alkoxymethyl,2-(C₃-C₆)cycloalkoxyethyl, (C₆-C₂₄)aryl, and (C₆-C₂₄)heteroaryl, wherein(C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl are optionally substituted with 1 to5 R₈ substituents, in particular, 1 or 2 R₈, selected from the groupconsisting of deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro and and(C₁-C₆)alkylsulfonyl; R₃, R₄, R₅ and R₆ are independently selected fromthe group consisting of hydrogen, methyl and trifluoromethyl.
 6. Thecompound of claim 1 wherein the compound is of Formula Ic:

or a stereoisomer, tautomer, isotope or salt thereof.
 7. The compound ofclaim 5 wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 8. The compound of claim 6wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 9. The compound of claim 1wherein the compound is of Formula Id:

or a stereoisomer, isotope or salt thereof, wherein R₁ is hydroxyl oramino; and R₁′ is selected from the group consisting of hydrogen anddeuterium; and R₂ is hydrogen, methyl or trifluoromethyl.
 10. Thecompound of claim 9 wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 11. A compound of FormulaII:

or a stereoisomer, tautomer, isotope or salt thereof, wherein: A, B, Dare independently Carbon or Nitrogen; R₁ is selected from the groupconsisting of hydrogen, deuterium, methyl, trideuteromethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, phenyl, (C₆-C₂₄)aryl, and(C₅-C₂₄)heteroaryl, wherein (C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl areoptionally substituted with 1 to 5 R₈ substituents wherein each R₈ isindependently selected from the group consisting of deuterium, halo,methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino,cyano, nitro, and (C₁-C₆)alkylsulfonyl, in particular, 1 or 2 R₈ areindependently selected from that group other than hydrogen, when R₁ issubstituted, and the other R₈ are hydrogen; R₁′ is selected from thegroup consisting of hydrogen and deuterium; R₂ is selected from thegroup consisting of hydrogen, deuterium, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloheteroalkyl, 2-(C₁-C₆)alkoxyethyl, 2-hydroxyethyl,2-(C₆-C₂₄)aryloxyethyl, bis(2-methoxyethyl), (C₁-C₆)alkoxymethyl,2-(C₃-C₆)cycloalkoxyethyl, (C₆-C₂₄)aryl, and (C₆-C₂₄)heteroaryl, wherein(C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl are optionally substituted with 1 to5 R₈ substituents independently selected from the group consisting ofdeuterium, halo, methyl, trideuteromethyl, trifluoromethyl,2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy,(C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,(C₆-C₂₄)arylamino, cyano, nitro, and (C₁-C₆)alkylsulfonyl; R₃ is absentif A is Nitrogen, or if A is Carbon, R₃ is selected from the groupconsisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl; R₄ is absent if B is Nitrogen, or if B is Carbon,R₄ is selected from the group consisting of hydrogen, deuterium, halo,methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino,cyano, nitro, and (C₁-C₆)alkylsulfonyl; R₅ is absent if D is Nitrogen,or if D is Carbon, R₅ is a substituent selected from the groupconsisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl; R₆ and R₇ are independently selected from thegroup consisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl; and wherein the indicated (*) carbon is in the R-or S-configuration.
 12. The compound of claim 11 wherein the compound isof Formula IIa:

or a stereoisomer, tautomer, isotope or salt thereof.
 13. The compoundof claim 11 wherein the compound is of Formula IIb:

or a stereoisomer, tautomer, isotope or salt thereof, wherein: each R₈is independently selected from the group consisting of hydrogen,deuterium, halo, methyl, trideuteromethyl, trifluoromethyl,2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy,(C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,(C₆-C₂₄)arylamino, cyano, nitro, and (C₁-C₆)alkylsulfonyl, inparticular, 1 or 2 R₈ are independently selected from that group otherthan hydrogen, when R₁ is substituted, and the other R₈ are hydrogen.14. The compound of claim 11 wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 15. The compound of claim 11wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 16. The compound of claim 11wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 17. A compound of FormulaIII:

or a stereoisomer, tautomer, isotope or salt thereof, wherein: A, B, Dare independently Carbon or Nitrogen; R₁ is selected from the groupconsisting of hydrogen, deuterium, methyl, trideuteromethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, phenyl, (C₆-C₂₄)aryl, and(C₅-C₂₄)heteroaryl, wherein (C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl areoptionally substituted with 1 to 5 R₈ substituents, wherein each R₈ isindependently selected from the group consisting of deuterium, halo,methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino,cyano, nitro, and (C₁-C₆)alkylsulfonyl, in particular, 1 or 2 R₈ areindependently selected from that group other than hydrogen, when R₁ issubstituted, and the other R₈ are hydrogen; R₁′ is selected from thegroup consisting of hydrogen and deuterium; R₂ is selected from thegroup consisting of hydrogen, deuterium, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloheteroalkyl, 2-(C₁-C₆)alkoxyethyl, 2-hydroxyethyl,2-(C₆-C₂₄)aryloxyethyl, bis(2-methoxyethyl), (C₁-C₆)alkoxymethyl,2-(C₃-C₆)cycloalkoxyethyl, (C₆-C₂₄)aryl, and (C₆-C₂₄)heteroaryl, wherein(C₆-C₂₄)aryl and (C₆-C₂₄)heteroaryl are optionally substituted with 1 to5 R₈ substituents independently selected from the group consisting ofdeuterium, halo, methyl, trideuteromethyl, trifluoromethyl,2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy,(C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,(C₆-C₂₄)arylamino, cyano, nitro, and (C₁-C₆)alkylsulfonyl; R₃ is absentif A is Nitrogen, or if A is Carbon, R₃ is selected from the groupconsisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl; R₄ is absent if B is Nitrogen, or if B is Carbon,R₄ is selected from the group consisting of hydrogen, deuterium, halo,methyl, trideuteromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,(C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino,cyano, nitro, and (C₁-C₆)alkylsulfonyl; R₅ is absent if D is Nitrogen,or if D is Carbon, R₅ is a substituent selected from the groupconsisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl; R₆ and R₇ are independently selected from thegroup consisting of hydrogen, deuterium, halo, methyl, trideuteromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkyloxy, (C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, (C₆-C₂₄)arylamino, cyano, nitro, and(C₁-C₆)alkylsulfonyl; and wherein the indicated (*) carbon is in the R-or S-configuration.
 18. The compound of claim 17 wherein the compound isof Formula IIIa:

or a stereoisomer, tautomer, isotope or salt thereof, wherein: each R₈is independently selected from the group consisting of hydrogen,deuterium, halo, methyl, trideuteromethyl, trifluoromethyl,2,2,2-trifluoroethyl, (C₂-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkyloxy,(C₃-C₆)cycloalkyloxy, amino, (C₁-C₆)alkylamino, di-(C₁-C₆)alkylamino,(C₆-C₂₄)arylamino, cyano, nitro, and (C₁-C₆)alkylsulfonyl, inparticular, 1 or 2 R₈ are independently selected from that group otherthan hydrogen, when R₁ is substituted, and the other R₈ are hydrogen.19. The compound of claim 18 wherein the compound is of Formula IIIb:

or a stereoisomer, tautomer, isotope or salt thereof.
 20. The compoundof claim 18 wherein the compound is of Formula IIIc:

or a stereoisomer, tautomer, isotope or salt thereof.
 21. The compoundof claim 18 wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 22. The compound of claim 18wherein the compound is:

or a stereoisomer, isotope or salt thereof.
 23. The compound of claim 1wherein the compound salt is that of a pharmaceutically acceptable saltwherein the pharmaceutically acceptable salt is an acid addition saltfrom hydrochloric, hydrobromic, phosphoric, phosphonic, nitric,sulfuric, acetic, chloroacetic, dichloroacetic, trichloroacetic,triflouroacetic, oxalic, maleic, mandelic, malonic, citric, tartaric,fumaric, salicylic, methanesulfonic, benzenesulfonic, toluenesulfonic,or 2,6-dimethylbenzenesulfonic acid.
 24. The compound of claim 1,wherein the compound is predominately in the R- or S-configuration atthe indicated (*) carbon.
 25. A composition comprising a compound ofclaim 1 and one, two, three or more compounds independently selectedfrom the group consisting of anesthetics, anti-arrhythmics,anticonvulsants, anti-antiarrhythmic peptides, anti-antiarrhythmicgrowth factors, anti-antiarrhythmic proteins, anti-antiarrhythmicdrug-peptide conjugates, antibody-drug conjugates, vitamins, andnutraceuticals.
 26. A drug delivery system for a compound of claim 1,wherein the drug delivery system is comprised of a component selectedfrom the group consisting of pharmaceutically accepted polymers,collagen, modified collagens, thrombin-collagen gels, starches, modifiedstarches, gels, hydrogels, pastes, colloids, suspensions, encapsulants,cyclodextrins, micelles, vesicles, and liposomes.
 27. A compositioncomprising a compound of claim 1 and isolated cells capable of acting onfunctional muscle cells, neuronal cells or cells of the central nervoussystem.
 28. The composition of claim 27 wherein the cells are progenitorcells or stem cells of induced, embryonic or adult origin.
 29. A methodof inhibiting sodium channels in animal cells found in living organismsor in isolated tissue cells comprising the step of contacting said cellswith an effective amount of a compound of claim
 1. 30. The method ofclaim 29 wherein inhibition of said sodium channels in animal cellsmodulate membrane potential, action potential or physiological functionwherein the animal cells are those of heart, brain, muscle, centralnervous system, or are peripheral cells.
 31. The method of claim 30,wherein the heart, brain, muscle, central nervous system, or peripheralcells are mature cells or progenitor cells.
 32. The method of claim 31wherein the progenitor cells are stem cells of induced, embryonic oradult origin.
 33. A method of inhibiting sodium channels in mammaliancells comprising the step of co-contacting the mammalian cells with aneffective amount of a compound claim 1 and an effective amount of ananti-arrhythmic drug.
 34. The method of claim 33, wherein theanti-arrhythmic drug is an ion channel inhibitor or agonist.
 35. Themethod of claim 34 wherein the anti-arrhythmic drug is a Class 1, Class2, Class 3, Class 4 or Class 5 anti-arrhythmic drug.
 36. A method ofinducing anesthetic, anti-arrhythmic, anticonvulsant oranti-hyperexcitability therapeutic effects in a subject in need thereofcomprising the steps of: (a) contacting isolated progenitor cells orstem cells of induced, embryonic cells or adult origin cells with aneffective amount of a compound of claim 1, and (b) administering aneffective number of cells of step (a) to the subject, OR comprising thestep of: (a′) co-administering an effective number of isolatedprogenitor cells or stem cells of induced, embryonic cells or adultorigin cells and an effective amount of a compound of claim 1 to thesubject.
 37. A method of inducing anesthetic, anti-arrhythmic,anticonvulsant or anti-hyperexcitability therapeutic effects in asubject in need thereof comprising the steps of: (a) co-contactingisolated progenitor cells or stem cells of induced, embryonic cells oradult origin cells with an effective amount of a compound of claim 1 andan effective amount of a chemical or biological agent selected from thegroup consisting of anesthetics, anti-arrhythmics, anticonvulsants,drugs, small molecules with ion channel antagonist effects, smallmolecules with ion channel agonist effects, anti-antiarrhythmicpeptides, anti-antiarrhythmic growth factors, anti-antiarrhythmicproteins, anti-antiarrhythmic drug-peptide conjugates, antibody-drugconjugates, vitamins, and nutraceuticals, and (b) administering aneffective number of cells of step (a) to the subject, OR, comprising thestep of: (a′) co-administering to the subject an effective number ofisolated cells and an effective amount of a compound of any one of claim1 and an effective amount of a chemical or biological agent selectedfrom the group consisting of anesthetics, anti-arrhythmics,anticonvulsants, drugs, small molecules with ion channel antagonisteffects, small molecules with ion channel agonist effects,anti-antiarrhythmic peptides, anti-antiarrhythmic growth factors,anti-antiarrhythmic proteins, anti-antiarrhythmic drug-peptideconjugates, antibody-drug conjugates, vitamins, and nutraceuticals. 38.A method for therapeutic modulation of a channelopathy or to induceanesthesia in a subject, comprising the step of administering aneffective amount of a compound claim 1 to the subject.
 39. The method ofclaim 38 wherein the channelopathy is a cardiac arrhythmia oramyotrophic lateral sclerosis or seizures.